Benzimidazole and azabenzimidazole compounds that inhibit anaplastic lymphoma kinase

ABSTRACT

Compounds of Formula (I) are useful inhibitors of anaplastic lymphoma kinase. Compounds of Formula (I) have the following structure: where the definitions of the variables are provided herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S.Provisional Application No. 61/371,041, filed on Aug. 5, 2010, which ishereby incorporated by reference in its entirety and for all purposes asif fully set forth herein.

FIELD OF THE INVENTION

The present invention relates to compounds capable of inhibiting thekinase activity of anaplastic lymphoma kinase (ALK), and compositionsthat include compounds that inhibit ALK. The compounds and compositionsmay be used to treat diseases or conditions modulated by ALK such ascancer and may be used to treat neurological disorders such asdepression and are especially useful in treating patients with cancersexpressing modified ALK or cancers related to ALK expression. Forexample, the compounds and compositions are especially useful intreating cancers that are positive for ALK fusion proteins EML4-ALKand/or NPM-ALK or have kinase activating point mutations in the ALKprotein as well as amplifications of the ALK locus on chromosome 2p23.

BACKGROUND OF THE INVENTION

ALK is a receptor tyrosine kinase conserved across species and plays akey role in the growth and differentiation of neural tissues in thedeveloping embryo. The receptor belongs in the insulin receptorsuperfamily and was initially identified as a member of a novelintracellular fusion protein with constitutive kinase activity inanaplastic large-cell lymphoma (ALCL). Bischof, D. et al., “Role of theNucleophosmin (NPM) Portion of the Non-Hodgkin's Lymphoma-AssociatedNPM-Anaplastic Lymphoma Kinase Fusion Protein in Oncogenesis,” Molecularand Cellular Biology. 17, 2312-2325 (1997); Pulford, K. et al., “TheEmerging Normal and Disease-Related Roles of Anaplastic LymphomaKinase,” Cell Mol Life Sci. 61, 2939-2953 (2004). Subsequent studieshave identified ALK fusion proteins in diffuse large B-cell lymphomas,systemic histiocytosis, inflammatory myofibroblastic tumors, breastcancers, colorectal carcinomas, and non-small cell lung cancers. Morris,S. W. et al., “Fusion of a Kinase Gene, ALK, to a Nucleolar ProteinGene, NPM, in Non-Hodgkin's Lymphoma”, Science (New York, N.Y. 263,1281-1284 (1994)); Lawrence, B. et al., “TPM3-ALK and TPM4-ALK Oncogenesin Inflammatory Myofibroblastic Tumors,” The American Journal ofPathology. 157, 377-384 (2000); Touriol, C. et al., “FurtherDemonstration of the Diversity of Chromosomal Changes Involving 2p23 inALK-Positive Lymphoma: 2 Cases Expressing ALK Kinase Fused to CLTCL(Clathrin Chain Polypeptide-Like),” Blood. 95, 3204-3207 (2000); Soda,M. et al., “Identification of the Transforming EML4-ALK Fusion Gene inNon-Small-Cell Lung Cancer,” Nature. 448, 561-566 (2007); Lin, E. etal., “Exon Array Profiling Detects EML4-ALK Fusion in Breast,Colorectal, and Non-Small Cell Lung Cancers,” Mol Cancer Res. 7,1466-1476 (2009). In addition, activating point mutations, as well asgenomic DNA amplification and overexpression of ALK have recently beendescribed in neuroblastomas. Mosse, Y. P. et al., “Identification of ALKas a Major Familial Neuroblastoma Predisposition Gene,” Nature. 455,930-935 (2008).

Using immunostaining and other methods, 60-80% of ALCLs have been foundto be ALK fusion-positive. Morris, S. W. et al., “Fusion of a KinaseGene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma”,Science (New York, N.Y. 263, 1281-1284 (1994)); Ladanyi, M. et al.,“Reverse Transcriptase Polymerase Chain Reaction for the Ki-1 AnaplasticLarge Cell Lymphoma-Associated t(2;5) Translocation in Hodgkin'sDisease,” The American Journal of Pathology. 145, 1296-1300 (1994).ALK-positive ALCL cells express the cell surface protein CD30 andexhibit a cytotoxic T-cell or null phenotype. This lymphoma entity isnow officially classified as ‘ALK-positive ALCL’ in the WHOclassification of NHL.

More recently, ALK has been identified in a subset of non small celllung carcinoma patients (NSCLC). In 2006, genetic analysis of a patientwith NSCLC led to the discovery of a novel fusion gene between theechinoderm microtubule-associated protein-like 4 (EML4) and theanaplastic lymphoma kinase (ALK) genes. Oncogenic activity of EML4-ALKrequires the N-terminal coiled-coil domain within EML4 that leads to theconstitutive dimerization and, thereby, activation of the fusionprotein. Soda, M. et al., “Identification of the Transforming EML4-ALKFusion Gene in Non-Small-Cell Lung Cancer,” Nature. 448, 561-566 (2007).Since both of the EML4 and ALK genes are closely mapped in an oppositedirection to the same short arm of human chromosome 2, a smallchromosome inversion involving the two genes is likely to be theunderlying mechanism for the generation of the gene fusion, which wasindeed evidenced by both of FISH and genomic PCR analyses.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,

wherein:

R¹ is —H;

R² is —H;

R³ is selected from —H, —F, —Cl, —Br, —I; —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl,—OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂, —N(H)—(C₁-C₆)alkyl,—N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH, —C(═O)O—(C₁-C₆)alkyl,—C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, —C(═O)N((C₁-C₆)alkyl)₂,—N(H)—C(═O)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-OH, —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-N(H)—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,or phenyl optionally substituted with 1, 2, or 3 substituents selectedfrom —F, —Cl, —Br, —I; —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂,—N(H)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH,—C(═O)O—(C₁-C₆)alkyl, —C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, or—C(═O)N((C₁-C₆)alkyl)₂;

X is selected from CR⁴ or N;

R⁴ is absent if X is N, or is selected from —H, —F, —Cl, —Br, —I;—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃, —OH, —OCF₃,—O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂, —N(H)—(C₁-C₆)alkyl,—N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH, —C(═O)O—(C₁-C₆)alkyl,—C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, —C(═O)N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-OH, —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-N(H)—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,or phenyl optionally substituted with 1, 2, or 3 substituents selectedfrom —F, —Cl, —Br, —I; —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂,—N(H)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH,—C(═O)O—(C₁-C₆)alkyl, —C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, or—C(═O)N((C₁-C₆)alkyl)₂;

Y is selected from a C₃-C₁₂ cycloalkyl or a 3-10 membered heterocyclylcomprising 1, 2, or 3 heteroatoms selected from O, S, or N; wherein theC₃-C₁₂ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic,bicyclic, or tricyclic, and further wherein the C₃-C₁₂ cycloalkyl andthe 3-10 membered heterocyclyl are unsubstituted or are optionallysubstituted with 1, 2, or 3 substituents independently selected from—Y′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —OH, —O—(C₁-C₆)alkyl, —SH,—S—(C₁-C₆)alkyl, —OCF₃, —OCHF₂, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂,—NHSO₂—(C₁-C₆)alkyl, —NHC(═O)—(C₁-C₆)alkyl, —C(═O)NH₂,—C(═O)NH((C₁-C₆)alkyl), —C(═O)NH—(C₁-C₄)alkylene-CF₃,—C(═O)NH—(C₁-C₄)alkylene-F, —C(═O)NH—(C₂-C₄)alkenyl,—C(═O)N((C₁-C₆)alkyl)₂, —C(═O)NH—OH, —C(═O)NH—O—(C₁-C₆)alkyl,—C(═O)NH—Y″, —C(═O)—(C₁-C₄)alkylene-CF₃, —C(═O)N—(C₁-C₄)alkylene-F,—C(═O)—(C₂-C₄)alkenyl, —C(═O)—(C₁-C₄)alkylene-NH₂,—C(═O)—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-Y″,—C(═O)—(C₁-C₆)alkyl, —C(═O)—Y″, —CO₂H, —C(═O)—O—(C₁-C₆)alkyl,—C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₆)alkyl), —SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₄)alkenyl),—SO₂NH((C₂-C₄)alkynyl), —SO₂NH—Y″, —SO₂NH—(C₁-C₄)alkylene-OH,—SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂—Y″,—SO—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-NH—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂-(C₁-C₄)alkylene-OH,—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, or —(C₁-C₄)alkylene-C(═O)—OH;wherein two substituents on a carbon ring member of the Y cycloalkyl orheterocyclyl may join to form a 3-7 membered cycloalkyl group or a 3-7membered heterocyclyl group that comprises 1 to 3 heteroatoms selectedfrom N, O, or S; and further wherein 1 or 2 carbon atom ring members ofthe 3-7 membered cycloalkyl or the 3-7 membered heterocyclyl groupformed from the two substituents on the carbon ring member of the Ycycloalkyl or heterocyclyl may be double bonded to an O atom;

Y′ may be absent or is a C₆-C₁₀ aryl, a 5-10 membered heteroarylcomprising 1, 2, 3, or 4 heteroatoms independently selected from O, S,or N, or a 3-7 membered heterocyclyl comprising 1, 2, or 3 heteroatomsselected from O, S, or N, wherein the C₆-C₁₀ aryl, the 5-10 memberedheteroaryl, or the 3-7 membered heterocyclyl Y′ groups are unsubstitutedor are optionally substituted with 1, 2, or 3 substituents independentlyselected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

Y″ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylY″ groups are unsubstituted or are optionally substituted with 1, 2, or3 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH,—NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂,—C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl,—NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

W is selected from —H, —F, —Cl, —Br, —I, —(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—OH, —(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—O—W′, —O—(CR^(a)R^(a′))_(q)—W′,—O—(CR^(a)R^(a′))_(q)—OH, —O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—OH,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—SH, —(CR^(a)R^(a′))_(q)—S—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—S—W′, —S—(CR^(a)R^(a′))_(q)—W′,—(CR^(a)R^(a′))_(q)—S(O)₂—(C₁-C₆)alkyl, —(CR^(a)R^(a′))_(q)—S(O)₂—W′,—S(O)₂—(CR^(a)R^(a′))_(q)—W′, —(CR^(a)R^(a′))_(q)—NH₂,—(CR^(a)R^(a′))_(q)—NH—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—N—((C₁-C₆)alkyl,)₂,—(CR^(a)R^(a′))_(q)—N⁺—((C₁-C₆)alkyl,)₃, —(CR^(a)R^(a′))_(q)—NH—W′,—(CR^(a)R^(a′))_(q)—NH—(CR^(a)R^(a′))_(q)—OH, —NH—(CR^(a)R^(a′))_(q)—W′,or —(CR^(a)R^(a′))_(q)—W′;

W′ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylW′ groups are unsubstituted or are optionally substituted with 1, 2, 3,or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N,—NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂,—CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂, —(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃,—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —SO₃H,—OCF₃, —OCHF₂, or —C(═O)—W″; and further wherein W′ may include 0, 1, or2 ═O groups when W′ is a C₃-C₁₀ cycloalkyl or a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom;

W″ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylW″ groups are unsubstituted or are optionally substituted with 1, 2, 3,or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N,—NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; andfurther wherein W″ may include 0, 1, or 2 ═O groups when W″ is a C₃-C₁₀cycloalkyl or a 3-10 membered heterocyclyl, and further wherein the ═Ogroups may be bonded to a ring carbon atom or a ring S atom;

the subscript q is, in each instance, independently selected from 0, 1,2, 3, or 4;

R^(a) is, in each instance, independently selected from —H, —CH₃,—CH₂CH₃, —F, —CF₃, or —C≡N;

R^(a′) is, in each instance, independently selected from —H, —CH₃,—CH₂CH₃, —F, —CF₃, or —C≡N; or R^(a) and R^(a′) may join to form acyclopropyl ring together with the carbon atom to which they areattached;

Z is selected from a C₆-C₁₀ aryl; a 5-10 membered heteroaryl comprising1, 2, 3 or 4 heteroatoms independently selected from O, S, or N; a 4-7membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O,S, or N; a C₃-C₇ cycloalkyl; a —N(H)-heterocyclyl, wherein theheterocyclyl of —N(H)-heterocyclyl is a 4-7 membered heterocyclylcomprising 1, 2, or 3 heteroatoms selected from O, S, or N;a-N(H)—(C₃-C₇)cycloalkyl; or Z is a —O—(C₁-C₆)alkyl; wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, the 4-7 membered heterocyclyl, theC₃-C₇ cycloalkyl; the —N(H)-heterocyclyl, and the—N(H)—(C₃-C₇)cycloalkyl are unsubstituted or are optionally substitutedwith 1, 2, or 3 substituents independently selected from —F, —Cl, —Br,—I, —C≡N, —NO₂, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂,—C(═O)NH₂, —C(═O)NH((C₁-C₆)alkyl), —C(═O)N((C₁-C₆)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₆)alkyl), —SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₆)alkenyl),—SO₂NH((C₂-C₆)alkynyl), —SO₂NH—(C₁-C₄)alkylene-OH,—SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —NHSO₂—(C₁-C₆)alkyl,—NHC(═O)—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl, —C(═O)—(C₁-C₆)alkyl, —CO₂H,—C(═O)—O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

W is not —H, —F, —Cl, —Br, —I, or unsubstituted —(C₁-C₆)alkyl if X isCR⁴;

Y is not unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl if W is—H, —F, —Cl, —Br, —I, or —(C₁-C₆)alkyl;

W is not —CH₂OH or —CH₂O(C₁-C₄alkyl) if Y is a group of formula

and

W is not —SH, —OH, —S—(C₁-C₆)alkyl), or —S—(C₁-C₆)alkyl) if Z is—O—(C₁-C₆)alkyl);

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, X is N.

In some embodiments, X is CR⁴. In some such embodiments, R⁴ is —H.

In some embodiments, R³ is —H.

In some embodiments, Z is selected from —OMe or —NH-cyclohexyl; or anunsubstituted or substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, piperidinyl, isothiazolyl, or thiomorpholinylgroup. In some such embodiments, Z is selected from —OMe or—NH-cyclohexyl; or an unsubstituted or substituted phenyl, pyridyl,benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

In some embodiments, Z is an unsubstituted or substituted phenyl,pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl,isothiazolyl, or thiomorpholinyl group. In some embodiments, Z is anunsubstituted or substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, or piperidinyl group. In some suchembodiments, Z is a substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, or piperidinyl group.

In some embodiments, Z is an unsubstituted or substituted phenyl orpyridyl. In some such embodiments, Z is a substituted phenyl or pyridyl.In some other such embodiments, Z is a substituted phenyl.

In some embodiments, Y is an unsubstituted or substituted cycloheptyl,cyclohexyl, cyclopentyl, cyclobutyl, piperidinyl, pyrrolidinyl,azetidinyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, orbicyclo[2.1.1]hexyl. In some such embodiments, Y is a substitutedcycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl, piperidinyl,pyrrolidinyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, orbicyclo[2.1.1]hexyl group. In some such embodiments, Y is anunsubstituted or substituted cyclohexyl. In some such embodiments, Y isa substituted cyclohexyl. In other such embodiments, Y is anunsubstituted or substituted adamantyl. In some such embodiments, Y isan unsubstituted adamantyl. In other embodiments, Y is a substitutedadamantyl. In other such embodiments, Y is an unsubstituted orsubstituted cyclobutyl. In some such embodiments, Y is a substitutedcyclobutyl. In still other embodiments, Y is an unsubstituted orsubstituted cyclopentyl or cycloheptyl. In some such embodiments Y is asubstituted cyclopentyl or cycloheptyl. In still other embodiments, Y isan unsubstituted or substituted piperidinyl. In some such embodiments, Yis a substituted piperidinyl. In some embodiments where Y issubstituted, Y is substituted with a group that includes a carbonyl(C═O) functional group. Examples include, but are not limited toketones, esters, and amides.

In some embodiments, W is selected from —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₂OH,—CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂OMe, —W′, —CH₂W′, —OW′, —OCH₂W′,—OCH₂CH₂W′, —OCH₂CH₂CH₂W′, —NHW′, —NHCH₂W′, —NHCH₂CH₂W′, —NHCH₂CH₂CH₂W′,or —W′—C(═O)—W″; wherein W′, if present, is selected from a 3-10membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O,and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3,or 4 heteroatoms independently selected from N, O, or S; wherein the3-10 membered heterocyclyl W′ group may be monocyclic or bicyclic, andfurther wherein the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, or the5-10 membered heteroaryl W′ groups are unsubstituted or are substitutedwith 1, 2, 3, or 4 substituents independently selected from —F, —Cl,—Br, —(C₁-C₆)alkyl, —CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH₂, —SO₂—(C₁-C₆)alkyl,—CF₃, —CO₂H, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, or —SO₃H; and further whereinW′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; and further wherein W″, if present, is a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may bemonocyclic or bicyclic, and further wherein the 3-10 memberedheterocyclyl W″ group is unsubstituted or is optionally substituted with1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I,—C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂, or apharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof.

In some embodiments, W is selected from —W′, —CH₂W′, —OW′, —OCH₂W′,—OCH₂CH₂W′, —OCH₂CH₂CH₂W′, —NHW′, —NHCH₂W′, —NHCH₂CH₂W′, —NHCH₂CH₂CH₂W′,or —W′—C(═O)—W″; wherein W′, is selected from a 3-10 memberedheterocyclyl comprising 1 or 2 heteroatoms selected from N, O, and S; aC₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4heteroatoms independently selected from N, O, or S; wherein the 3-10membered heterocyclyl W′ group may be monocyclic or bicyclic, andfurther wherein the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, or the5-10 membered heteroaryl W′ groups are unsubstituted or are substitutedwith 1, 2, 3, or 4 substituents independently selected from —F, —Cl,—Br, —(C₁-C₆)alkyl, —CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH₂, —SO₂—(C₁-C₆)alkyl,—CF₃, —CO₂H, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, or —SO₃H; and further whereinW′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; and further wherein W″, if present, is a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may bemonocyclic or bicyclic, and further wherein the 3-10 memberedheterocyclyl W″ group is unsubstituted or is optionally substituted with1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I,—C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂.

In some embodiments, W is not —H, —F, —Cl, —OH, or —OMe.

In some embodiments of any of those described above, the compound is apharmaceutically acceptable salt of the compound, a tautomer of thecompound, a pharmaceutically acceptable salt of the tautomer, astereoisomer of any of the foregoing, or is a mixture of any of these.In some such embodiments, the compound is a tautomer. In some suchembodiments, the compound is a pharmaceutically acceptable salt of thetautomer. In still other embodiments, the compound is a singlestereoisomer whereas in other embodiments, the compound is a mixture ofenantiomers or is a mixture of stereoisomers and such a mixture mayinclude equal or unequal amount of specific stereioisomers. In someembodiments, the compound is a racemic mixture of stereoisomers.

In some embodiments, the compound is any one of the Example compounds.

In some embodiments, the compound is a salt. Such salts may be anhydrousor associated with water as a hydrate.

In some embodiments, the compound is a prodrug.

Also provided are pharmaceutical formulations that include at least onepharmaceutically acceptable carrier, excipient or diluent and atherapeutically effective amount of the compound of any of theembodiments described herein. In some such embodiments, the compound ispresent in an amount effective for the treatment of cancer.

Further provided are pharmaceutical formulations that include at leastone pharmaceutically acceptable carrier, and a therapeutically effectiveamount of the composition of matter of any of the embodiments describedherein in combination with at least one additional compound such as acytotoxic agent or a compound that inhibits another kinase.

In other embodiments, the invention provides a method of treatingcancer. Such methods typically include administering to a subject aneffective amount of a compound of any one of the embodiments or apharmaceutical composition that includes any of the compounds of any ofthe embodiments. In some such embodiments, the subject has a cancer thatexpresses an ALK fusion protein, point mutation, or overexpression. Inother such embodiments, the ALK fusion protein is EML4-ALK fusionprotein or NPM-ALK fusion protein. In some embodiments, the subject is ahuman cancer patient, and the cancer is selected from adenocarcinoma,lung cancer, non-small cell lung carcinoma, breast cancer, colorectalcancer, lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma,glioblastoma diffuse large B-cell lymphomas, systemic histiocytosis, orinflammatory myofibroblastic tumors. In some such embodiments, thecancer is non-small cell lung carcinoma (NSCLC). In some embodiments,the cancer is an EML4-ALK positive cancer or is a NPM-ALK positivecancer.

In still other embodiments, the invention provides a method of treatinga condition where it is desired to inhibit ALK activity. Such methodstypically include administering to a subject an effective amount of acompound of any of the embodiments or a pharmaceutical composition thatincludes a compound of any of the embodiments.

In some embodiments, the compound of any of the embodiments is used inthe preparation of a medicament. In some such embodiments, themedicament is for use in treating cancer. In some such embodiments, amedicament is for use in inhibiting ALK. In still other suchembodiments, the medicament is for use in treating a cancer thatexpresses an ALK fusion protein. In some such embodiments, the ALKfusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. Insome such embodiments, the ALK fusion protein is EML4-ALK fusionprotein. In other such embodiments, the ALK fusion protein is NPM-ALKfusion protein.

In some such embodiments, a compound or pharmaceutical formulation ofany of the embodiments is provided for use in treating cancer. In somesuch embodiments, the cancer expresses an ALK fusion protein. In somesuch embodiments, the ALK fusion protein is EML4-ALK fusion protein orNPM-ALK fusion protein. In some such embodiments, the ALK fusion proteinis EML4-ALK fusion protein. In other such embodiments, the ALK fusionprotein is NPM-ALK fusion protein. In some embodiments, a compound orpharmaceutical formulation of any of the embodiments is provided for usein treating cancer and the cancer is selected from adenocarcinoma, lungcancer, non-small cell lung carcinoma, breast cancer, colorectal cancer,lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma,glioblastoma diffuse large B-cell lymphomas, systemic histiocytosis, orinflammatory myofibroblastic tumors. In some such embodiments, thecancer is non-small cell lung carcinoma (NSCLC). In still otherembodiments, a compound or pharmaceutical formulation of any of theembodiments is provided for use in inhibiting ALK or for use in treatinga disease or condition wherein inhibition of ALK is desired.

Other objects, features and advantages of the invention will becomeapparent to those skilled in the art from the following description andclaims.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thestandard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemicalformula, its definition on each occurrence is independent of itsdefinition at every other occurrence. If the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds of the present disclosure maycontain one or more chiral centers and/or double bonds and therefore,may exist as stereoisomers, such as double-bond isomers (i.e., geometricisomers), enantiomers or diastereomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intothe component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.

Certain compounds of the invention may possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, enantiomers,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the invention. Furthermore,atropisomers and mixtures thereof such as those resulting fromrestricted rotation about two aromatic or heteroaromatic rings bonded toone another are intended to be encompassed within the scope of theinvention, where, and if, appropriate.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line from one atom to the other indicates that bothstereoisomers are encompassed. A wavy line drawn across a bond,indicates point of attachment of a group to the rest of the molecule.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers, mixtures ofdiastereomers or enantiomerically or optically pure compounds. Thisinvention encompasses the use of stereomerically pure forms of suchcompounds, as well as the use of mixtures of those forms. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular compound of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tablesof Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

Compounds of the invention may exist in multiple tautomeric forms. Theseforms are illustrated below as “Tautomer A” and “Tautomer B”:

Because one chemical structure may only be used to represent onetautomeric form, it will be understood that for convenience, referral toa compound of a given structural formula includes tautomers of thestructure represented by the structural formula. Furthermore, thecompounds may exist as mixtures of tautomers in equal or unequal amountsor may exist solely in one tautomeric form. The same may apply to saltsand stereoisomers.

Compounds of the present disclosure include, but are not limited to,compounds of Formula I and all pharmaceutically acceptable formsthereof. Pharmaceutically acceptable forms of the compounds recitedherein include pharmaceutically acceptable salts, solvates, crystalforms (including polymorphs and clathrates), chelates, non-covalentcomplexes, prodrugs, and mixtures thereof. In certain embodiments, thecompounds described herein are in the form of pharmaceuticallyacceptable salts. As used herein, the term “compound” encompasses notonly the compound itself, but also a pharmaceutically acceptable saltthereof, a solvate thereof, a chelate thereof, a non-covalent complexthereof, a prodrug thereof, and mixtures of any of the foregoing. Insome embodiments, the term “compound” encompasses the compound itself,pharmaceutically acceptable salts thereof, tautomers of the compound,pharmaceutically acceptable salts of the tautomers, and ester prodrugssuch as (C₁-C₄)alkyl esters. In other embodiments, the term “compound”encompasses the compound itself, pharmaceutically acceptable saltsthereof, tautomers of the compound, pharmaceutically acceptable salts ofthe tautomers.

As noted above, prodrugs also fall within the scope of chemicalentities, for example, ester or amide derivatives of the compounds ofFormula I. The term “prodrugs” includes any compounds that becomecompounds of Formula I when administered to a patient, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate, benzoate, carbomethoxy,carboethoxy and like derivatives of functional groups (such as alcohol,carboxylic acid, ether, ester, or amine groups) in the compounds ofFormula I.

The term “solvate” refers to the compound formed by the interaction of asolvent and a compound. Suitable solvates are pharmaceuticallyacceptable solvates, such as hydrates, including monohydrates andhemi-hydrates.

Certain structures are drawn to include standard abbreviations such asMe to represent methyl and Et to represent ethyl. Other structures maybe drawn such that H atoms are not shown on hydroxyl groups or Ncontaining groups where the N is singly bonded to two othersubstituents. It will be recognized that such compounds include a H atsuch locations. Finally, some structures may be drawn that include abond that does not show the terminal carbon as CH₃ or Me. It will berecognized that such structures include a CH₃ group in such compounds.

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic or prophylactic agents, research reagents, e.g., GPR40 assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe invention. For example, if a variable is said to be H, this meansthat variable may also be deuterium (D) or tritium (T).

“ALK” refers to anaplastic lymphoma kinase, tyrosine kinase. ALK wasoriginally identified as part of the chimeric nucleophosmin-ALK proteinin the t(2;5) chromosomal rearrangement associated with anaplastic largecell lymphoma.

“EML4-ALK fusion protein” refers to a protein that results from a fusionof echinoderm microtubule-associated protein-like 4 (EML4) and ALK.

“NPM-ALK fusion protein” refers to a protein that results from a fusionof nucleophosmin (NPM) with ALK.

“Alkyl” refers to a saturated, branched or straight-chain monovalenthydrocarbon group derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkyl groups include, butare not limited to, methyl, ethyl, propyls such as propan-1-yl,propan-2-yl, and butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl,and the like. In certain embodiments, an alkyl group comprises 1 to 20carbon atoms. In some embodiments, alkyl groups include 1 to 6 carbonatoms whereas in other embodiments, alkyl groups include 1 to 4 carbonatoms. In still other embodiments, an alkyl group includes 1 or 2 carbonatoms. Branched chain alkyl groups include at least 3 carbon atoms andtypically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms.An alkyl group having 1 to 6 carbon atoms may be referred to as a—(C₁-C₆)alkyl group and an alkyl group having 1 to 4 carbon atoms may bereferred to as a —(C₁-C₄)alkyl.

“Alkenyl” refers to an unsaturated branched or straight-chainhydrocarbon group having at least one carbon-carbon double bond derivedby the removal of one hydrogen atom from a single carbon atom of aparent alkene. The group may be in either the Z- or E-form (cis ortrans) about the double bond(s). Typical alkenyl groups include, but arenot limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl(allyl), and prop-2-en-2-yl; butenyls suchas but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, andbuta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenylgroup has 2 to 20 carbon atoms and in other embodiments, has 2 to 6carbon atoms. An alkenyl group having 2 to 6 carbon atoms may bereferred to as a —(C₂-C₆)alkenyl group

“Alkynyl” refers to an unsaturated branched or straight-chainhydrocarbon having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and thelike. In certain embodiments, an alkynyl group has 2 to 20 carbon atomsand in other embodiments, has 2 to 6 carbon atoms. An alkynyl grouphaving 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkynyl group

“Alkoxy” refers to a radical —OR where R represents an alkyl group asdefined herein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. Typicalalkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbonatoms may be designated as —O(C₁₋₆) alkyl or as —O—(C₁₋₆) alkyl groups.In some embodiments, an alkoxy group may include 1 to 4 carbon atoms andmay be designated as an —O(C₁₋₄) alkyl or as an —O—(C₁₋₄) alkyl group.

“Alkylene” refers to a divalent saturated hydrocarbon group derived froma parent alkane by removal of two hydrogen atoms. Examples of alkylenegroup include, but are not limited to, —CH₂—, —CH₂CH₂—, —CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)—, and the like, and may include acyclic hydrocarbon group such as a —CH(cyclopropyl)-alkylene group. Insome embodiments an alkylene may include 1 to 6 carbon atoms and inother embodiments may include 1 to 4 carbon atoms. Such groups may bedesignated as —(C₁-C₆)alkylene- and —(C₁-C₄)alkylene- groups.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl encompasses monocyclic carbocyclic aromaticrings, for example, benzene; bicyclic ring systems wherein at least onering is carbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene. Aryl groups may includefused ring systems where one ring is a carbocyclic aromatic ring and theother ring(s) are not aromatic and may be heterocyclic or carcocyclic.For example, aryl groups include systems where a carbocyclic aromaticring is fused to a 5- to 7-membered heterocyclic ring containing 1 ormore heteroatoms chosen from N, O, and S. In certain embodiments, anaryl group includes 6 to 10 carbon atoms. Such groups may be referred toas C₆-C₁₀ aryl groups. Aryl, however, does not encompass or overlap inany way with heteroaryl as separately defined below. Hence, if one ormore carbocyclic aromatic rings is fused with a heterocyclic aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein. Bicyclic and tricyclic aryl groups include at least one ringthat is aromatic. The other rings in such systems may be partiallyunsaturated. For example, tetralin (1,2,3,4-tetrahydronaphthalene)includes a benzene ring fused to a ring that includes saturation and istherefore, partially saturated. Examples of other aryl groups with apartially saturated ring include, but are not limited to, indane,1,4-dihydronaphthalene, chroman, 2,3-dihydrobenzo[b][1,4]dioxine,1,2,3,4-tetrahydroquinoline, and indoline. The nonaromatic rings of suchsystems may also include a carbon that is double-bonded to an O.Examples of such aryl groups include, but are not limited to,2-indanone, 1-indanone, 3,4-dihydronaphthalen-2(1H)-one, chroman-3-one,indolin-2-one, and 1,2-dihydroquinolin-3(4H)-one.

“Carbonyl” refers to the radical —C(O) or —C(═O) group.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN which can also be represented by —C≡N.

“Cycloalkyl” refers to a saturated or partially unsaturated, butnon-aromatic, cyclic alkyl group. Where a specific level of saturationis intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used.Typical cycloalkyl groups include, but are not limited to, groupsderived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, andthe like. In certain embodiments, the cycloalkyl group can be C₃₋₁₀cycloalkyl, such as, for example, C₃₋₆ cycloalkyl. In some embodiments,a cycloalkyl group is a saturated cycloalkyl group.

“Heterocyclic”, “heterocyclo” or “heterocyclyl” refer to saturated orpartially unsaturated, but non-aromatic, cyclic hydrocarbon groups inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or a different heteroatom and itsassociated hydrogen atoms, where appropriate. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, O, and S.In some embodiments, a heterocyclyl group includes 3 to 10 ring membersof which 1, 2, or 3 ring members are independently selected from N, O,or S. In other embodiments, a heterocyclyl group includes 5 to 7 ringmembers of which 1, 2, or 3 are heteroatoms independently selected fromN, O, or S. Typical heterocyclyl groups include, but are not limited to,groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran,tetrahydropyran and the like. Substituted heterocyclyl also includesring systems substituted with one or more oxo (═O) or oxide (—O⁻)substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

“Disease” refers to any disease, disorder, condition, symptom, orindication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen isreplaced with a halogen. Thus, the term “haloalkyl” includesmonohaloalkyl (alkyl substituted with one halogen atom) andpolyhaloalkyl (alkyl substituted with two or more halogen atoms). Theterm “perhaloalkyl” means, unless otherwise stated, an alkyl group inwhich each of the hydrogen atoms is replaced with a halogen atom. Forexample, the term “perhaloalkyl”, includes, but is not limited to,trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Heteroaryl groups typically include 5- to10-membered aromatic, monocyclic and bicyclic rings containing one ormore, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3,heteroatoms chosen from N, O, and S, with the remaining ring atoms beingcarbon. The term heteroaryl may also encompass tricyclic ring systemscontaining one or more, for example, 1, 2, 3, or 4, or in certainembodiments, 1, 2, or 3, heteroatoms chosen from N, O, and S, with theremaining ring atoms being carbon and wherein at least one heteroatom ispresent in an aromatic ring. For example, heteroaryl includes a 5- to7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkylring or to a carbocyclic aromatic ring or to a 5-7 memberedheteroaromatic ring, and heteroaryl includes a 5- to 7-memberedheteroaromatic ring fused to a 5- to 7-membered heterocyclic ring. Forfused, bicyclic heteroaryl ring systems wherein only one of the ringscontains one or more heteroatoms, the point of attachment may be at theheteroaromatic ring or the carbocyclic ring. When the total number of Sand O atoms in the heteroaryl group exceeds 1, those heteroatoms are notadjacent to one another. In certain embodiments, the total number of Sand O atoms in the heteroaryl group is not more than 2. In certainembodiments, the total number of S and O atoms in the aromaticheterocycle is not more than 1. Heteroaryl does not encompass or overlapwith aryl as defined above. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, carbazole, β-carboline,cinnoline, furan, imidazole, indazole, indole, indolizine,isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. Incertain embodiments, the heteroaryl group can be between 5 to 20membered heteroaryl, such as, for example, a 5 to 10 memberedheteroaryl. In certain embodiments, heteroaryl groups can be thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, andpyrazine.

“Sulfonyl” refers to a radical —S(O)₂R where R is an alkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocyclyl, substitutedaryl, or substituted heteroaryl group as defined herein. Representativeexamples include, but are not limited to, methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, and the like.

“Sulfanyl” refers to a radical —SR where R is an alkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocyclyl, substitutedaryl, or substituted heteroaryl group as defined herein that may beoptionally substituted as defined herein. Representative examplesinclude, but are not limited to, methylthio, ethylthio, propylthio,butylthio, and the like.

“Pharmaceutically acceptable” refers to generally recognized for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, and the like; or (2) salts formed when an acidicproton present in the parent compound either is replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient,” “pharmaceutically acceptablecarrier,” or “pharmaceutically acceptable adjuvant” refer, respectively,to an excipient, carrier or adjuvant with which at least one compound ofthe present disclosure is administered. “Pharmaceutically acceptablevehicle” refers to any of a diluent, adjuvant, excipient or carrier withwhich at least one compound of the present disclosure is administered.

“Stereoisomer” refers to an isomer that differs in the arrangement ofthe constituent atoms in space. Stereoisomers that are mirror images ofeach other and optically active are termed “enantiomers,” andstereoisomers that are not mirror images of one another and areoptically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject”are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease or disorder, is sufficient toaffect such treatment for the disease, disorder, or symptom. The“therapeutically effective amount” can vary depending on the compound,the disease, disorder, and/or symptoms of the disease or disorder,severity of the disease, disorder, and/or symptoms of the disease ordisorder, the age of the subject to be treated, and/or the weight of thesubject to be treated. An appropriate amount in any given instance canbe readily apparent to those skilled in the art or capable ofdetermination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, or inhibiting at leastone physical parameter which may not be discernible to the subject.Further, “treating” or “treatment” refers to delaying the onset of thedisease or disorder or at least symptoms thereof in a subject which maybe exposed to or predisposed to a disease or disorder even though thatsubject does not yet experience or display symptoms of the disease ordisorder.

Reference will now be made in detail to embodiments of the presentdisclosure. While certain embodiments of the present disclosure will bedescribed, it will be understood that it is not intended to limit theembodiments of the present disclosure to those described embodiments. Tothe contrary, reference to embodiments of the present disclosure isintended to cover alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the embodiments of the presentdisclosure as defined by the appended claims.

In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,

wherein:

R¹ is —H;

R² is —H;

R³ is selected from —H, —F, —Cl, —Br, —I; —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl,—OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂, —N(H)—(C₁-C₆)alkyl,—N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH, —C(═O)O—(C₁-C₆)alkyl,—C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, —C(═O)N((C₁-C₆)alkyl)₂,—N(H)—C(═O)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-OH, —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-N(H)—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,or phenyl optionally substituted with 1, 2, or 3 substituents selectedfrom —F, —Cl, —Br, —I; —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂,—N(H)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH,—C(═O)O—(C₁-C₆)alkyl, —C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, or—C(═O)N((C₁-C₆)alkyl)₂;

X is selected from CR⁴ or N;

R⁴ is absent if X is N, or is selected from —H, —F, —Cl, —Br, —I;—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃, —OH, —OCF₃,—O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂, —N(H)—(C₁-C₆)alkyl,—N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH, —C(═O)O—(C₁-C₆)alkyl,—C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, —C(═O)N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-OH, —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-N(H)—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,or phenyl optionally substituted with 1, 2, or 3 substituents selectedfrom —F, —Cl, —Br, —I; —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—CF₃, —OH, —OCF₃, —O—(C₁-C₆)alkyl, —OCHF₂, —SH, —S—(C₁-C₆)alkyl, —NH₂,—N(H)—(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —NO₂, —C≡N, —C(═O)OH,—C(═O)O—(C₁-C₆)alkyl, —C(═O)NH₂, —C(═O)N(H)—(C₁-C₆)alkyl, or—C(═O)N((C₁-C₆)alkyl)₂;

Y is selected from a C₃-C₁₂ cycloalkyl or a 3-10 membered heterocyclylcomprising 1, 2, or 3 heteroatoms selected from O, S, or N; wherein theC₃-C₁₂ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic,bicyclic, or tricyclic, and further wherein the C₃-C₁₂ cycloalkyl andthe 3-10 membered heterocyclyl are unsubstituted or are optionallysubstituted with 1, 2, or 3 substituents independently selected from—Y′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —OH, —O—(C₁-C₆)alkyl, —SH,—S—(C₁-C₆)alkyl, —OCF₃, —OCHF₂, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂,—NHSO₂—(C₁-C₆)alkyl, —NHC(═O)—(C₁-C₆)alkyl, —C(═O)NH₂,—C(═O)NH((C₁-C₆)alkyl), —C(═O)NH—(C₁-C₄)alkylene-CF₃,—C(═O)NH—(C₁-C₄)alkylene-F, —C(═O)NH—(C₂-C₄)alkenyl,—C(═O)N((C₁-C₆)alkyl)₂, —C(═O)NH—OH, —C(═O)NH—O—(C₁-C₆)alkyl,—C(═O)NH—Y″, —C(═O)—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-F,—C(═O)—(C₂-C₄)alkenyl, —C(═O)—(C₁-C₄)alkylene-NH₂,—C(═O)—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-Y″,—C(═O)—(C₁-C₆)alkyl, —C(═O)—Y″, —CO₂H, —C(═O)—O—(C₁-C₆)alkyl,—C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₆)alkyl), —SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₄)alkenyl),—SO₂NH((C₂-C₄)alkynyl), —SO₂NH—Y″, —SO₂NH—(C₁-C₄)alkylene-OH,—SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂—Y″,—SO—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-NH—C(═O)(C₁-C₆)alkyl,—(C₁-C₄)alkylene-NH—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂-(C₁-C₄)alkylene-OH,—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, or —(C₁-C₄)alkylene-C(═O)—OH;wherein two substituents on a carbon ring member of the Y cycloalkyl orheterocyclyl may join to form a 3-7 membered cycloalkyl group or a 3-7membered heterocyclyl group that comprises 1 to 3 heteroatoms selectedfrom N, O, or S; and further wherein 1 or 2 carbon atom ring members ofthe 3-7 membered cycloalkyl or the 3-7 membered heterocyclyl groupformed from the two substituents on the carbon ring member of the Ycycloalkyl or heterocyclyl may be double bonded to an O atom;

Y′ may be absent or is a C₆-C₁₀ aryl, a 5-10 membered heteroarylcomprising 1, 2, 3, or 4 heteroatoms independently selected from O, S,or N, or a 3-7 membered heterocyclyl comprising 1, 2, or 3 heteroatomsselected from O, S, or N, wherein the C₆-C₁₀ aryl, the 5-10 memberedheteroaryl, or the 3-7 membered heterocyclyl Y′ groups are unsubstitutedor are optionally substituted with 1, 2, or 3 substituents independentlyselected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

Y″ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylY″ groups are unsubstituted or are optionally substituted with 1, 2, or3 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH,—NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂,—C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl,—NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

W is selected from —H, —F, —Cl, —Br, —I, —(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—OH, —(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—O—W′, —O—(CR^(a)R^(a′))_(q)—W′,—O—(CR^(a)R^(a′))_(q)—OH, —O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—OH,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—SH, —(CR^(a)R^(a′))_(q)—S—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—S—W′, —S—(CR^(a)R^(a′))_(q)—W′,—(CR^(a)R^(a′))_(q)—S(O)₂—(C₁-C₆)alkyl, —(CR^(a)R^(a′))_(q)—S(O)₂—W′,—S(O)₂—(CR^(a)R^(a′))_(q)—W′, —(CR^(a)R^(a′))_(q)—NH₂,—(CR^(a)R^(a′))_(q)—NH—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—N—((C₁-C₆)alkyl,)₂,—(CR^(a)R^(a′))_(q)—N⁻—((C₁-C₆)alkyl,)₃, —(CR^(a)R^(a′))_(q)—NH—W′,—(CR^(a)R^(a′))_(q)—NH—(CR^(a)R^(a′))_(q)—OH, —NH—(CR^(a)R^(a′))_(q)—W′,or —(CR^(a)R^(a′))_(q)—W′;

W′ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylW′ groups are unsubstituted or are optionally substituted with 1, 2, 3,or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N,—NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂,—CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂, —(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃,—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —SO₃H,—OCF₃, —OCHF₂, or —C(═O)—W″; and further wherein W′ may include 0, 1, or2 ═O groups when W′ is a C₃-C₁₀ cycloalkyl or a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom;

W″ may be absent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from N,O, and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from N, O, or S; wherein theC₃-C₁₀ cycloalkyl and the 3-10 membered heterocyclyl may be monocyclicor bicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylW″ groups are unsubstituted or are optionally substituted with 1, 2, 3,or 4 substituents independently selected from —F, —Cl, —Br, —I, —C≡N,—NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; andfurther wherein W″ may include 0, 1, or 2 ═O groups when W″ is a C₃-C₁₀cycloalkyl or a 3-10 membered heterocyclyl, and further wherein the ═Ogroups may be bonded to a ring carbon atom or a ring S atom;

the subscript q is, in each instance, independently selected from 0, 1,2, 3, or 4;

R^(a) is, in each instance, independently selected from —H, —CH₃,—CH₂CH₃, —F, —CF₃, or —C≡N;

R^(a′) is, in each instance, independently selected from —H, —CH₃,—CH₂CH₃, —F, —CF₃, or —C≡N; or R^(a) and R^(a′) may join to form acyclopropyl ring together with the carbon atom to which they areattached;

Z is selected from a C₆-C₁₀ aryl; a 5-10 membered heteroaryl comprising1, 2, 3 or 4 heteroatoms independently selected from O, S, or N; a 4-7membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O,S, or N; a C₃-C₇ cycloalkyl; a —N(H)-heterocyclyl, wherein theheterocyclyl of —N(H)-heterocyclyl is a 4-7 membered heterocyclylcomprising 1, 2, or 3 heteroatoms selected from O, S, or N;a-N(H)—(C₃-C₇)cycloalkyl; or Z is a —O—(C₁-C₆)alkyl; wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, the 4-7 membered heterocyclyl, theC₃-C₇ cycloalkyl; the —N(H)-heterocyclyl, and the—N(H)—(C₃-C₇)cycloalkyl are unsubstituted or are optionally substitutedwith 1, 2, or 3 substituents independently selected from —F, —Cl, —Br,—I, —C≡N, —NO₂, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂,—C(═O)NH₂, —C(═O)NH((C₁-C₆)alkyl), —C(═O)N((C₁-C₆)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₆)alkyl), —SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₆)alkenyl),—SO₂NH((C₂-C₆)alkynyl), —SO₂NH—(C₁-C₄)alkylene-OH,—SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —NHSO₂—(C₁-C₆)alkyl,—NHC(═O)—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl, —C(═O)—(C₁-C₆)alkyl, —CO₂H,—C(═O)—O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

W is not —H, —F, —Cl, —Br, —I, or unsubstituted —(C₁-C₆)alkyl if X isCR⁴;

Y is not unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl if W is—H, —F, —Cl, —Br, —I, or —(C₁-C₆)alkyl;

W is not —CH₂OH or —CH₂O(C₁-C₄alkyl) if Y is a group of formula

and

W is not —SH, —OH, —S—(C₁-C₆)alkyl), or —S—(C₁-C₆)alkyl) if Z is—O—(C₁-C₆)alkyl);

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, X is N.

In some embodiments, X is CR⁴. In some such embodiments, R⁴ is —H.

In some embodiments, R³ is —H.

In some embodiments, Z is selected from —OMe or —NH-cyclohexyl; or anunsubstituted or substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, piperidinyl, isothiazolyl, or thiomorpholinylgroup. In some such embodiments, Z is selected from —OMe or—NH-cyclohexyl; or an unsubstituted or substituted phenyl, pyridyl,benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

In some embodiments, Z is an unsubstituted or substituted phenyl,pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl,isothiazolyl, or thiomorpholinyl group. In some embodiments, Z is anunsubstituted or substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, or piperidinyl group. In some suchembodiments, Z is a substituted phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, or piperidinyl group.

In some embodiments, Z is an unsubstituted or substituted phenyl orpyridyl. In some such embodiments, Z is a substituted phenyl or pyridyl.In some other such embodiments, Z is a substituted phenyl.

In some embodiments, Z is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, Z is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, Y is an unsubstituted or substituted cycloheptyl,cyclohexyl, cyclopentyl, cyclobutyl, piperidinyl, pyrrolidinyl,azetidinyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, orbicyclo[2.1.1]hexyl. In some such embodiments, Y is a substitutedcycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl, piperidinyl,pyrrolidinyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, orbicyclo[2.1.1]hexyl group. In some such embodiments, Y is anunsubstituted or substituted cyclohexyl. In some such embodiments, Y isa substituted cyclohexyl. In other such embodiments, Y is anunsubstituted or substituted adamantyl. In some such embodiments, Y isan unsubstituted adamantyl. In other embodiments, Y is a substitutedadamantyl. In other such embodiments, Y is an unsubstituted orsubstituted cyclobutyl. In some such embodiments, Y is a substitutedcyclobutyl. In still other embodiments, Y is an unsubstituted orsubstituted cyclopentyl or cycloheptyl. In some such embodiments Y is asubstituted cyclopentyl or cycloheptyl. In still other embodiments, Y isan unsubstituted or substituted piperidinyl. In some such embodiments, Yis a substituted piperidinyl. In some embodiments where Y issubstituted, Y is substituted with a group that includes a carbonyl(C═O) functional group. Examples include, but are not limited toketones, esters, and amides.

In some embodiments, Y is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, Y is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, Y is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, Y is wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, W is selected from —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₂OH,—CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂OMe, —W′, —CH₂W′, —OW′, —OCH₂W′,—OCH₂CH₂W′, —OCH₂CH₂CH₂W′, —NHW′, —NHCH₂W′, —NHCH₂CH₂W′, —NHCH₂CH₂CH₂W′,or —W′—C(═O)—W″; wherein W′, if present, is selected from a 3-10membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O,and S; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3,or 4 heteroatoms independently selected from N, O, or S; wherein the3-10 membered heterocyclyl W′ group may be monocyclic or bicyclic, andfurther wherein the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, or the5-10 membered heteroaryl W′ groups are unsubstituted or are substitutedwith 1, 2, 3, or 4 substituents independently selected from —F, —Cl,—Br, —(C₁-C₆)alkyl, —CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH₂, —SO₂—(C₁-C₆)alkyl,—CF₃, —CO₂H, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, or —SO₃H; and further whereinW′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; and further wherein W″, if present, is a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may bemonocyclic or bicyclic, and further wherein the 3-10 memberedheterocyclyl W″ group is unsubstituted or is optionally substituted with1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I,—C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂, or apharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof.

In some embodiments, W is selected from —W′, —CH₂W′, —OW′, —OCH₂W′,—OCH₂CH₂W′, —OCH₂CH₂CH₂W′, —NHW′, —NHCH₂W′, —NHCH₂CH₂W′, —NHCH₂CH₂CH₂W′,or —W′—C(═O)—W″; wherein W′, is selected from a 3-10 memberedheterocyclyl comprising 1 or 2 heteroatoms selected from N, O, and S; aC₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4heteroatoms independently selected from N, O, or S; wherein the 3-10membered heterocyclyl W′ group may be monocyclic or bicyclic, andfurther wherein the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, or the5-10 membered heteroaryl W′ groups are unsubstituted or are substitutedwith 1, 2, 3, or 4 substituents independently selected from —F, —Cl,—Br, —(C₁-C₆)alkyl, —CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH₂, —SO₂—(C₁-C₆)alkyl,—CF₃, —CO₂H, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, or —SO₃H; and further whereinW′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; and further wherein W″, if present, is a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may bemonocyclic or bicyclic, and further wherein the 3-10 memberedheterocyclyl W″ group is unsubstituted or is optionally substituted with1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I,—C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂.

In some embodiments, W is selected from —H, —F, —Cl, —OH, —OMe, —SO₂Me,—CH₂OH, —CH₂OMe, —OCH₂CH₂OH, —OCH₂CH₂OMe, or a group selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, W is not —H, —F, —Cl, —OH, or —OMe.

In some embodiments, W is selected from —OH, —SO₂Me, —CH₂OH, —CH₂OMe,—OCH₂CH₂OH, —OCH₂CH₂OMe, or a group selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, W is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.

In some embodiments, the compound is selected from

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof.

In some embodiments of any of those described above, the compound is apharmaceutically acceptable salt of the compound, a tautomer of thecompound, a pharmaceutically acceptable salt of the tautomer, astereoisomer of any of the foregoing, or is a mixture of any of these.In some such embodiments, the compound is a tautomer. In some suchembodiments, the compound is a pharmaceutically acceptable salt of thetautomer. In still other embodiments, the compound is a singlestereoisomer whereas in other embodiments, the compound is a mixture ofenantiomers or is a mixture of stereoisomers and such a mixture mayinclude equal or unequal amount of specific stereioisomers. In someembodiments, the compound is a racemic mixture of stereoisomers.

In some embodiments, the compound is any one of the Example compounds.

In some embodiments, the compound is a salt. Such salts may be anhydrousor associated with water as a hydrate.

In some embodiments, the compound is a prodrug.

Also provided are pharmaceutical formulations that include at least onepharmaceutically acceptable carrier, excipient or diluent and atherapeutically effective amount of the compound of any of theembodiments described herein. In some such embodiments, the compound ispresent in an amount effective for the treatment of cancer.

Further provided are pharmaceutical formulations that include at leastone pharmaceutically acceptable carrier, and a therapeutically effectiveamount of the composition of matter of any of the embodiments describedherein in combination with at least one additional compound such as acytotoxic agent or a compound that inhibits another kinase.

In other embodiments, the invention provides a method of treatingcancer. Such methods typically include administering to a subject aneffective amount of a compound of any one of the embodiments or apharmaceutical composition that includes any of the compounds of any ofthe embodiments. In some such embodiments, the subject has a cancer thatexpresses an ALK fusion protein. In other such embodiments, the ALKfusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. Insome embodiments, the subject is a human cancer patient, and the canceris selected from adenocarcinoma, lung cancer, non-small cell lungcarcinoma, breast cancer, colorectal cancer, lymphoma, neuroblastoma,ovarian cancer, mesothelioma, melanoma, glioblastoma, diffuse largeB-cell lymphomas, systemic histiocytosis, or inflammatorymyofibroblastic tumors. In some such embodiments, the cancer isnon-small cell lung carcinoma (NSCLC).

In still other embodiments, the invention provides a method of treatinga condition where it is desired to inhibit ALK activity. Such methodstypically include administering to a subject an effective amount of acompound of any of the embodiments or a pharmaceutical composition thatincludes a compound of any of the embodiments.

In some embodiments, the compound of any of the embodiments is used inthe preparation of a medicament. In some such embodiments, themedicament is for use in treating cancer. In some such embodiments, amedicament is for use in inhibiting ALK. In still other suchembodiments, the medicament is for use in treating a cancer thatexpresses an ALK fusion protein. In some such embodiments, the ALKfusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. Insome such embodiments, the ALK fusion protein is EML4-ALK fusionprotein. In other such embodiments, the ALK fusion protein is NPM-ALKfusion protein.

In some such embodiments, a compound or pharmaceutical formulation ofany of the embodiments is provided for use in treating cancer. In somesuch embodiments, the cancer expresses an ALK fusion protein. In somesuch embodiments, the ALK fusion protein is EML4-ALK fusion protein orNPM-ALK fusion protein. In some such embodiments, the ALK fusion proteinis EML4-ALK fusion protein. In other such embodiments, the ALK fusionprotein is NPM-ALK fusion protein. In some embodiments, a compound orpharmaceutical formulation of any of the embodiments is provided for usein treating cancer and the cancer is selected from adenocarcinoma, lungcancer, non-small cell lung carcinoma, breast cancer, colorectal cancer,lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma,glioblastoma, diffuse large B-cell lymphomas, systemic histiocytosis, orinflammatory myofibroblastic tumors. In some such embodiments, thecancer is non-small cell lung carcinoma (NSCLC). In still otherembodiments, a compound or pharmaceutical formulation of any of theembodiments is provided for use in inhibiting ALK or for use in treatinga disease or condition wherein inhibition of ALK is desired.

In one embodiment, the invention provides a method of treating aproliferation-related disorder in a mammal in need thereof. Such methodsinclude administering to the mammal a therapeutically effective amountof a compound of any of the embodiments described herein or apharmaceutical composition comprising the compound. Another embodimentof the invention comprises treating abnormal cell growth byadministering a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition of the invention to a subjectin need thereof. In some embodiments, the invention provides the use ofa compound of any of the embodiments or a pharmaceutical composition ofthe invention for treating abnormal cell growth. The abnormal cellgrowth can be a benign growth or a malignant growth. In particular, theabnormal cell growth can be a carcinoma, sarcoma, lymphoma, or leukemia.In one embodiment of this method, the abnormal cell growth is a cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. The method of the invention also comprises treating apatient having cancer wherein the cancer is selected from the groupconsisting of small cell lung carcinoma, non-small cell lung carcinoma,esophageal cancer, kidney cancer, pancreatic cancer, melanoma, bladdercancer, breast cancer, colon cancer, liver cancer, lung cancer, sarcoma,stomach cancer, cholangiocarcinoma, mesothelioma, or prostate cancer. Inanother embodiment of said method, said abnormal cell growth is a benignproliferative disease, including, but not limited to, psoriasis, benignprostatic hypertrophy or restenosis.

The pharmaceutical compositions or formulations for the administrationof the compounds of this invention may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart. All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition, the active object compound is includedin an amount sufficient to produce the desired effect upon the processor condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The compounds of the invention may be used to treat or prevent variouskinase-related disorders. Thus, the present invention provides methodsfor treating or preventing such disorders. In some embodiments, theinvention provides a method for treating a kinase-mediated disorder in asubject that includes administering a therapeutically effective amountof a compound of any of the embodiments of the invention or apharmaceutical composition to the subject. In some embodiments, thesubject is a mammal, and in some such embodiments is a human. In someembodiments the disorder is mediated by IGF-1R, Insulin Receptor, ALKKDR, Tie2, EGFR, PKA, PKB, PKC, FKHR, TSC1/2, SGK, LCK, BTK, Erk, MSK,MK2, MSK, p38, P70S6K, PIM1, PIM2, ROCK2, GSK3, JAK, or a CDK complex.In some such embodiments, the disorder is mediated by a JAK familymember such as JAK2. In other such embodiments, the disorder is mediatedby ALK. In some such embodiments, the administration of the compound orpharmaceutical composition produces selective inhibition of ALK. In someembodiments, the disorder is cancer. The present invention thus providesmethods for treating or preventing ALK-mediated disease states, such ascancer. In some embodiments, the cancer is a tumor such as a solidtumor.

The compounds of the invention may also be used to treatproliferation-related disorders. Thus, the invention further providesmethods for treating such proliferation-related disorders in a subject.Such methods include administering to a subject in need thereof atherapeutically effective amount of the compound or pharmaceuticalcomposition of any of the embodiments. In some embodiments, the subjectis a mammal. In some such embodiments, the mammal is a human. In someembodiments, the proliferation-related disorder is abnormal cell growth.In other embodiments, the disorder is inflammation or aninflammation-related disorder. In still other embodiments, the disorderis a metabolic disease such as diabetes. In still other embodiments, thedisorder is cancer. In some such embodiments, the cancer is a solidtumor.

The magnitude of a prophylactic or therapeutic dose of a compound of anyof the embodiments or a pharmaceutically acceptable salt, solvate,hydrate, or stereoisomer thereof in the acute or chronic treatment orprevention of a cancer or other disease or condition will vary with thenature and aggressiveness of the condition, and the route by which theactive ingredient is administered. The dose, and in some cases the dosefrequency, will also vary according to the condition to be treated, theage, body weight, and response of the individual patient. Suitabledosing regimens can be readily selected by those skilled in the art withdue consideration of such factors. In one embodiment, the doseadministered depends upon the specific compound to be used, and theweight and condition of the patient. In general, the dose per day is inthe range of from about 0.001 to 100 mg/kg, preferably about 1 to 25mg/kg, more preferably about 1 to about 5 mg/kg. For treatment of humanshaving a cancer, about 0.1 mg to about 15 g per day is administered inabout one to four divisions a day, preferably 10 mg to 12 g per day,more preferably from 40 mg to 500 mg per day. In one embodiment thecompounds of the invention are administered from 40 mg to 500 mg per dayin about one to four divisions a day. Additionally, the recommendeddaily dose can be administered in cycles as single agents or incombination with other therapeutic agents. In one embodiment, the dailydose is administered in a single dose or in equally divided doses. In arelated embodiment, the recommended daily dose can be administered onetime per week, two times per week, three times per week, four times perweek or five times per week.

The compounds of the invention can be administered to provide systemicdistribution of the compound within the patient. Therefore, in someembodiments, the compounds of the invention are administered to producea systemic effect in the body.

The compounds of the invention may also be administered directly to asite affected by a condition, as, for example, an in the treatment of anaccessible area of skin or an esophageal cancer.

As indicated above, the compounds of the invention may be administeredvia oral, mucosal (including sublingual, buccal, rectal, nasal, orvaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In some embodiments, the compounds of the invention areadministered via mucosal (including sublingual, buccal, rectal, nasal,or vaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In other embodiments, the compounds of the invention areadministered via oral administration. In still other embodiments, thecompounds of the invention are not administered via oral administration.

Different therapeutically effective amounts may be applicable fordifferent conditions, as will be readily known by those of ordinaryskill in the art. Similarly, amounts sufficient to treat or prevent suchconditions, but insufficient to cause, or sufficient to reduce, adverseeffects associated with conventional therapies are also encompassed bythe above described dosage amounts and dose frequency schedules.

Some methods of the invention comprise the administration of a compoundof the invention and an additional therapeutic agent (i.e., atherapeutic agent other than a compound of the invention). Thus, thecompounds of the invention can be used in combination with at least oneother therapeutic agent. Examples of additional therapeutic agentsinclude, but are not limited to, antibiotics, anti-emetic agents,antidepressants, antifungal agents, anti-inflammatory agents,antineoplastic agents, antiviral agents, cytotoxic agents, and otheranticancer agents, immunomodulatory agents, alpha-interferons,β-interferons, alkylating agents, hormones, and cytokines. In oneembodiment, the invention encompasses administration of an additionaltherapeutic agent that demonstrates anti-cancer activity. In anotherembodiment, an additional therapeutic agent that demonstrates cytotoxicactivity is administered to a subject such as a cancer patient.

The compounds of the invention and the other therapeutics agent can actadditively or, preferably, synergistically. In some embodiments, acomposition comprising a compound of the invention is administeredconcurrently with the administration of another therapeutic agent, whichcan be part of the same composition or can be in a different compositionfrom the one that comprises the compound of the invention. In otherembodiments, a compound of the invention is administered prior to, orsubsequent to, administration of another therapeutic agent. In stillother embodiments, a compound of the invention is administered to apatient who has not previously undergone or is not currently undergoingtreatment with another therapeutic agent. A compound of the inventionmay be administered to a subject that has had, is currently undergoing,or is scheduled to receive radiation therapy. In some such embodiments,the subject is a cancer patient.

When administered as a combination, the therapeutic agents can beformulated as separate compositions that are administered at the sametime or sequentially at different times, or the therapeutic agents canbe given as a single composition. The phrase “co-therapy” (or“combination-therapy”), in defining use of a compound of the presentinvention and another pharmaceutical agent, is intended to embraceadministration of each agent in a sequential manner in a regimen thatwill provide beneficial effects of the drug combination, and is intendedas well to embrace co-administration of these agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofthese active agents or in multiple, separate capsules for each agent.Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof any of the embodiments described herein may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. The invention is not limitedin the sequence of administration as compounds of the invention may beadministered either prior to, simultaneous with, or after administrationof a known anticancer or cytotoxic agent.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which maybe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

A first family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom, but are not limited to, the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT, and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from, but are not limited to, thegroup consisting of Shionogi 254-S, aldo-phosphamide analogues,altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139,Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, AmericanCyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, SumimotoDACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erbadistamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, ErbamontFCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M,Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine,mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCINSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119,ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin, and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from, but are not limited to, the group consisting ofTaiho 4181-A, aclarubicin, actinomycin D, actinoplanone, ErbamontADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3,Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC₈₉-A1, Kyowa HakkoDC₉₂-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and zorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from, but not limited to, thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, andYamanouchi YM-534.

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as acemannan, aclarubicin,aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HITdiclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin,edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetinbeta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim,finasteride, fludarabine phosphate, formestane, fotemustine, galliumnitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafurcombination, glycopine, goserelin, heptaplatin, human chorionicgonadotropin, human fetal alpha fetoprotein, ibandronic acid,idarubicin, (imiquimod, interferon alfa, interferon alfa, natural,interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferonalfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha,natural, interferon beta, interferon beta-1a, interferon beta-1b,interferon gamma, natural interferon gamma-1a, interferon gamma-1b,interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole,leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil,liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mismatched doublestranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim,nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,noscapine, novel erythropoiesis stimulating protein, NSC 631570octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronicacid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RIIretinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide,bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

The compounds of the invention may further be used with VEGFRinhibitors. Other compounds described in the following patents andpatent applications can be used in combination therapy: U.S. Pat. No.6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat. No. 6,235,764, WO01/32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat.No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S.Pat. No. 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279,WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO 00/12089, and WO00/02871.

In some embodiments, the combination comprises a composition of thepresent invention in combination with at least one anti-angiogenicagent. Agents are inclusive of, but not limited to, in vitrosynthetically prepared chemical compositions, antibodies, antigenbinding regions, radionuclides, and combinations and conjugates thereof.An agent can be an agonist, antagonist, allosteric modulator, toxin or,more generally, may act to inhibit or stimulate its target (e.g.,receptor or enzyme activation or inhibition), and thereby promote celldeath or arrest cell growth.

Exemplary anti-tumor agents include HERCEPTIN™ (trastuzumab), which maybe used to treat breast cancer and other forms of cancer, and RITUXAN™(rituximab), ZEVALIN™ (ibritumomab tiuxetan), and LYMPHOCIDE™(epratuzumab), which may be used to treat non-Hodgkin's lymphoma andother forms of cancer, GLEEVEC™ which may be used to treat chronicmyeloid leukemia and gastrointestinal stromal tumors, and BEXXAR™(iodine 131 tositumomab) which may be used for treatment ofnon-Hodgkins's lymphoma.

Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR(kinase domain receptor) inhibitory agents (e.g., antibodies and antigenbinding regions that specifically bind to the kinase domain receptor),anti-VEGF agents (e.g., antibodies or antigen binding regions thatspecifically bind VEGF, or soluble VEGF receptors or a ligand bindingregion thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptoragents (e.g., antibodies or antigen binding regions that specificallybind thereto), EGFR inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto) such as ABX-EGF(panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 andanti-Ang2 agents (e.g., antibodies or antigen binding regionsspecifically binding thereto or to their receptors, e.g., Tie2/Tek), andanti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen bindingregions that specifically bind thereto). The pharmaceutical compositionsof the present invention can also include one or more agents (e.g.,antibodies, antigen binding regions, or soluble receptors) thatspecifically bind and inhibit the activity of growth factors, such asantagonists of hepatocyte growth factor (HGF, also known as ScatterFactor), and antibodies or antigen binding regions that specificallybind its receptor “c-met”.

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tekantagonists (Ceretti et al., U.S. Publication No. 2003/0162712; U.S.Pat. No. 6,413,932), anti-TWEAK agents (e.g., specifically bindingantibodies or antigen binding regions, or soluble TWEAK receptorantagonists; see, Wiley, U.S. Pat. No. 6,727,225), ADAM distintegrindomain to antagonize the binding of integrin to its ligands (Fanslow etal., U.S. Publication No. 2002/0042368), specifically binding anti-ephreceptor and/or anti-ephrin antibodies or antigen binding regions (U.S.Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447;6,057,124 and patent family members thereof), and anti-PDGF-BBantagonists (e.g., specifically binding antibodies or antigen bindingregions) as well as antibodies or antigen binding regions specificallybinding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g.,antibodies or antigen binding regions that specifically bind thereto).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer,USA); cilengitide. (Merck KGaA, Germany, EPO 770622); pegaptaniboctasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA,(Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat, (Arriva, USA, U.S.Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783);vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA);TLC ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab,(Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem, Canada);Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan);SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070);ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson,USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor,(Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236,(Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA);angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan);2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00,(IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan);TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelialgrowth factor antagonist, (Borean, Denmark); cancer therapy, (Universityof South Carolina, USA); bevacizumab (pINN), (Genentech, USA);angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647,(Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (AppliedMolecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy,(Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA);CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (GenoaInstitute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia,Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derivedantiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide(pINN), (Merck KGaA, German; Munich Technical University, Germany,Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis,France); AVE 8062, (Ajinomoto, Japan); AS 1404, (Cancer ResearchLaboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (BostonChildrens Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (BostonChildrens Hospital, USA); 2-methoxyestradiol, (Boston ChildrensHospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (AngiogenePharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca,UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis,Switzerland and Schering AG, Germany); tissue factor pathway inhibitors,(EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA);xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based,VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2,(Supratek, Canada); SDX 103, (University of California at San Diego,USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I,(Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE,USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C,(British Columbia University, Canada); CDP 791, (Celltech Group, UK);atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine,angiogenesis, (EntreMed, USA); urokinase plasminogen activatorinhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA);HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA);KR 31372, (Korea Research Institute of Chemical Technology, SouthKorea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA);786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drugdelivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA);anginex, (Maastricht University, Netherlands, and Minnesota University,USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,(ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (NationalInstitute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (BostonChildrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems,USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor,(Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (SouthFlorida University, USA and Yale University, USA); CS 706, (Sankyo,Japan); combretastatin A4 prodrug, (Arizona State University, USA);chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925,(Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA); GCS100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD 732,(Chong Kun Dang, South Korea); MAb, vascular endothelium growth factor,(Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG 13577,(Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN),(Genaera, USA); RPI 4610, (Sirna, USA); cancer therapy, (Marinova,Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon,South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG,Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis,Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102,(Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA);VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin, (NationalInstitutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); truncatedsoluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck &Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as VEGF antagonists, otherkinase inhibitors including p38 inhibitors, c-met inhibitors, KDRinhibitors, EGF inhibitors and CDK inhibitors, TNF inhibitors, matrixmetalloproteinases (MMP) inhibitors, COX-2 inhibitors includingcelecoxib, NSAID's, or α_(v)β₃ inhibitors.

The compounds of the invention can be prepared using the generalsynthetic routes shown below in Scheme 1, Scheme 2, and Scheme 3 anddescribed more fully in the Examples.

As shown in Schemes 1 and 2, Y-substituted4-amino-2-chloro-5-nitropyridines provide excellent access to compoundsof Formula I where X is N. As shown in Schemes 1 and 2, nucleophiles,such as 2-(piperidin-1-yl)ethanol (Example 20) or morpholine (seeExample 222) can be reacted with Y-substituted4-amino-2-chloro-5-nitropyridine compounds to displace the chlorinegroup and form the appropriate bond to a selected W group. Reduction ofthe nitro group to an amine using hydrogenation conditions followed byreaction with a selected isothiocyanate such as 4-fluorobenzoylisothiocyanate (see Example 222) to form the five-membered ring andprovide the appropriate Z group allows ready access to the compounds ofFormula I where X is N.

As shown in Scheme 3, (3-fluoro-4-nitrophenyl)methanol provides aconvenient starting material for the preparation of various compounds ofFormula I where X is C. For example, an amine nucleophile bearing aselected Y group such as N-(cis-4-aminocyclohexyl)isobutyramide (seeExample 227) may be reacted with (3-fluoro-4-nitrophenyl)methanol toform the Y substituted (3-amino-4-nitrophenyl)methanol compound.Reduction of the nitro group to form the amino compound followed byreaction with an appropriate isothiocyanate such as 4-benzoylisothiocyanate (see Example 227) forms the five-membered ring and addsthe desired Z group to provide a useful hydroxymethyl compound that canbe readily converted to various compounds of Formula I. For example, thehydroxymethyl compound may be converted to a reactive chloromethylintermediate by reaction with thionyl chloride. The chloromethylintermediate may then be reacted with an appropriate nucleophile such as2-(piperidin-4-yl)propan-2-ol (see Example 227) to obtain the compoundof Formula I.

Modification of the above Schemes can be used to synthesize numerouscompounds of the invention as will be apparent to those skilled in theart.

The invention is further described by reference to the followingexamples, which are intended to exemplify the claimed invention but notto limit it in any way.

EXAMPLES

Unless otherwise stated, all starting material compounds and reagentswere obtained from commercial sources, including, but not limited to,Sigma Aldrich, Alfa Aesar, Oakwood, TCI America, Fluka, Frontier,AstaTech, Strem, Maybridge, Ark Pharma, Acros Organics, Combi-Blocks,Lancaster, Enamine, Matrix, and JRD Fluorochemicals, or were preparedusing known synthetic procedures, or were prepared using the methods andexperimental procedures described herein.

The following Abbreviations are used to refer to various reagents andsolvents:

-   -   ACN Acetonitrile    -   AcOH Acetic Acid    -   CDI Carbonyldiimidazole    -   DBU 1,8-Diazabicycloundec-7-ene    -   DCE Dichloroethane    -   DCM Dichloromethane    -   DIPEA Diisopropylethylamine    -   DMF N,N-Dimethylformamide    -   DMSO Dimethylsulfoxide    -   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   EtOAc Ethyl Acetate    -   EtOH Ethanol    -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HCl Hydrochloric acid    -   HOBT 1-Hydroxybenzotriazole    -   IPA Isopropanol    -   MeOH Methanol    -   NaHCO₃ Sodium bicarbonate    -   NaOH Sodium hydroxide    -   NH₄Cl Ammonium chloride    -   NMP N-methyl-2-pyrrolidone    -   NMR Nuclear Magnetic Resonance Spectroscopy    -   PS Polystyrene    -   RT Room Temperature    -   TEA Triethylamine    -   TBAF Tetrabutylammonium fluoride    -   THF Tetrahydrofuran    -   TFA Trifluoroacetic acid

EXAMPLES Example 1

cis-Methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

Step A: cis-Methyl 4-aminocyclohexanecarboxylate

A resealable pressure bottle was charged withcis-4-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol), MeOH (100 mL),and sulfuric acid (7.45 mL, 140 mmol). The vessel was sealed and themixture stirred at 80° C. for 24 hours. The mixture was cooled to 0° C.via an ice bath and made basic with NH₄OH to a pH of approximately 10.The aqueous layer was extracted with DCM (4×50 mL) and the organiclayers combined, dried over sodium sulfate and concentrated to affordcis-methyl 4-aminocyclohexanecarboxylate (9 g, 82% yield) as a colorlessoil. MS m/z=158.2 [M+H]. Calc'd for C₈H₁₅NO₂: 157.1.

Step B: cis-Methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate

A round bottom flask under nitrogen atmosphere was charged with4-chloro-3-nitropyridine (1.65 g, 10.41 mmol), cis-ethyl4-aminocyclohexanecarboxylate (2.454 g, 15.61 mmol), and ACN (26 mL). Tothe mixture was added DIPEA (3.63 mL, 20.81 mmol). The resulting mixturewas stirred at 60° C. for 17 hours. The reaction was stopped, cooled toRT and diluted with water (20 mL) and DCM (50 mL). The layers wereseparated, and the organic layer was collected, dried over sodiumsulfate and concentrated to afford an orange oil. The oil was purifiedby silica gel chromatography to afford the title compound (2.2 g, 76%yield) as a bright yellow solid. MS m/z=280.2 [M+H]. Calc'd forC₁₃H₁₇N₃O₄: 279.1.

Step C: cis-Methyl 4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate

A round bottom flask under nitrogen atmosphere was charged withcis-methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.1 g,3.94 mmol) and Pd/C (10% wt) (0.419 g, 0.394 mmol). EtOH (16 mL) wasadded, and the reaction mixture was purged with nitrogen 3 times. AH₂-filled balloon was attached to the top of the flask, and the mixturestirred at RT for 2 hours. The reaction mixture was diluted with EtOHand filtered through Celite® brand filter aid. The pad was washed withDCM (50 mL), EtOH (50 mL), and MeOH (50 mL). The filtrate wasconcentrated to dryness to afford cis-methyl4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate as a purple oil. (0.9g, 92.0% yield). MS m/z=250.2 [M+H]. Calc'd for C₁₃H₁₉N₃O₂: 249.2.

Step D: cis-Methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

To a solution of cis-methyl4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (70 mg, 0.281 mmol)in ACN (5.6 mL) under nitrogen was added benzoyl isothiocyanate (0.045mL, 0.337 mmol). The reaction mixture was stirred for 30 minutes at RT.To the mixture was added polymer-supported-carbodiimide (936 mg, 1.123mmol; Loading: 1.2 mmol/g;), and the resulting mixture was stirred at70° C. for 16 hours. The reaction mixture was cooled to RT and filtered,and the resin was washed with 1% MeOH/DCM. The filtrate was concentratedand purified by silica gel chromatography (1-4% MeOH/DCM) to affordcis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateas an off-white solid (18 mg, 17% yield). MS m/z=379.2 [M+H]. Calc'd forC₂₁H₂₂N₄O₃: 378.2.

Example 2

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

Step A: (3-Fluoro-4-nitrobenzyloxy)triisopropylsilane

To a 3-L round-bottomed flask was added (3-fluoro-4-nitrophenyl)methanol(4.7 g, 27.5 mmol) and DCM (47 mL). To the mixture was addedtriisopropylsilyl trifluoromethanesulfonate (9.26 g, 30.2 mmol) and2,6-dimethylpyridine (3.53 g, 33.0 mmol). The resulting mixture wasstirred for 3 hours at RT, and washed with NH₄Cl (5-250 mL) and H₂O(5-250 mL). The organic layer was collected and dried over sodiumsulfate and concentrated to afford(3-fluoro-4-nitrobenzyloxy)triisopropylsilane (8.9 g, 99% yield) as alight yellow oil.

Step B: cis-Methyl4-(2-nitro-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate

The title compound was prepared from(3-fluoro-4-nitrobenzyloxy)triisopropylsilane using the preparation forcis-methyl 4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate describedabove. The yield was 3.5 g (39.2% yield).

Step C: cis-Methyl4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate

A round bottom flask under nitrogen atmosphere was charged withcis-methyl4-(2-nitro-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate(2.77 g, 5.96 mmol) and palladium (10% on carbon) (0.634 g, 0.596 mmol).To this was added EtOH (48.5 mL) followed by ammonium formate (3.76 g,59.6 mmol). The reaction mixture was stirred at RT for 2 hours and thendiluted with EtOH and filtered through Celite® brand filter aid. Thefilter cake was washed sequentially with DCM (100 mL), EtOH (100 mL),and MeOH (100 mL). The filtrate was concentrated, re-diluted with DCM(100 mL) and washed with brine. The organic layer was collected, driedover sodium sulfate and concentrated to afford cis-methyl4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylateas a brown oil (2.58 g, 100% yield). MS m/z=435.2 [M+H]. Calc'd forC₂₄H₄₂N₂O₃Si: 434.3.

Step D: cis-Methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

A round bottom flask under nitrogen atmosphere was charged withcis-methyl4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate(2.5 g, 5.75 mmol) and EtOH (23.96 mL) To this was added cyanogenbromide (0.914 g, 8.63 mmol), and the reaction mixture was stirredovernight at RT. The reaction mixture was diluted with DCM (80 mL) andwashed with 1N aqueous NaOH (50 mL). The organic layer was collected,dried over sodium sulfate, and concentrated to dryness to affordcis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateas a brown solid (2.64 g, 100% yield). MS m/z=460.2 [M+H]. Calc'd forC₂₅H₄₁N₃O₃Si: 459.3.

Step E: cis-Methyl4-(2-(4-fluorobenzamido)-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

A solution of 4-fluorobenzoyl chloride (0.113 mL, 0.957 mmol) in DCM(2.90 mL) was cooled to 0° C. under nitrogen. To this was addedcis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.4 g, 0.870 mmol) followed by TEA (0.482 mL, 3.48 mmol). The resultingmixture was stirred at 0° C. for 30 minutes. The ice bath was removed,and the mixture was stirred for 2 hours. The reaction mixture wasdiluted with DCM (20 mL) and washed with water (10 mL). The organiclayer was collected, dried over sodium sulfate, concentrated, and driedunder vacuum to afford cis-methyl4-(2-(4-fluorobenzamido)-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.5 g, 100% yield).

Step F: cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-((triisopropylsilyloxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.61 g, 1.048 mmol) was suspended in 2.1 mL of THF and cooled to 0° C.under nitrogen. To this mixture was added TBAF (1 M in THF) (1.573 mL,1.573 mmol) dropwise via syringe, and the resulting mixture was stirredfor 30 minutes at 0° C. The ice bath was removed, and the mixture wasstirred for another 30 minutes at RT. The resulting mixture was dilutedwith DCM and washed with water. The organic layer was collected, driedover sodium sulfate, and concentrated, and the residue was purified bysilica gel chromatography (30-50% EtOAc/Hexanes) to provide the titlecompound (190 mg, 42.6% yield). MS m/z=426.2 [M+H]. Calc'd forC₂₃H₂₄FN₃O₄: 425.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63-1.92 (m, 4H)2.15-2.30 (m, 2H) 2.53-2.74 (m, 2H) 2.78-2.94 (m, 1H) 3.76 (s, 3H) 4.58(d, J=5.58 Hz, 2H) 4.62-4.82 (m, 1H) 5.24 (t, J=5.58 Hz, 1H) 7.11-7.20(m, 1H) 7.20-7.33 (m, 2H) 7.35-7.66 (m, 2H) 7.84-8.46 (m, 2H) 12.78 (s,1H).

Example 3

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

cis-Methyl4-(2-(4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.19 g, 0.447 mmol) was suspended in DCM (4.47 mL) and cooled to 0° C.under a nitrogen atmosphere. To this mixture was added thionyl chloride(0.652 mL, 8.93 mmol) dropwise, and the reaction mixture was stirred at0° C. for 1 hour. The ice bath was removed, and the mixture was stirredat RT for 2 hours. The reaction mixture was concentrated under reducedpressure and dried under high vacuum to afford a yellow foam. The foamwas suspended in 2 mL of DMSO and treated with piperidine (0.441 mL,4.47 mmol) followed by TEA (0.248 mL, 1.786 mmol). The resulting mixturewas stirred at RT for 2 hours. The reaction mixture was diluted with DCM(2-20 mL) and washed with water (2-20 mL). The organic layer wascollected, dried over sodium sulfate, and concentrated. The residue waspurified by HPLC (10-70% ACN/H₂O; 0.1% TFA) to afford cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateas a white solid (150 mg, 68.2% yield). MS m/z=493.2 [M+H]. Calc'd forC₂₈H₃₃FN₄O₃: 492.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.45 (m, 2H)1.44-1.61 (m, 4H) 1.66-1.93 (m, 4H) 2.19-2.32 (m, 2H) 2.29-2.43 (m, 4H)2.53-2.65 (m, 2H) 2.81-2.94 (m, 1H) 3.51 (s, 2H) 3.78 (s, 3H) 4.57-4.89(m, 1H) 7.10-7.18 (m, 1H) 7.21-7.32 (m, 2H) 7.42-7.52 (m, 2H) 8.02-8.48(m, 2H) 12.78 (s, 1H).

Example 4

cis-Methyl4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 2 steps from (cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(430 mg, 48.8% yield). MS m/z=408.2 [M+H]. Calc'd for C₂₃H₂₅N₃O₄: 407.2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.91 (m, 4H) 2.20-2.33 (m, 2H)2.55-2.73 (m, 2H) 2.77-2.93 (m, 1H) 3.22-3.48 (m, 1H) 3.77 (s, 3H) 4.56(s, 2H) 4.63-4.82 (m, 1H) 7.17-7.23 (m, 1H) 7.42-7.58 (m, 5H) 7.95-8.37(m, 2H) 12.82 (s, 1H).

Example 5

cis-Methyl4-(2-benzamido-6-(morpholinomethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(60 mg, 36.6% yield). MS m/z=477.2 [M+H]. Calc'd for C₂₇H₃₂N₄O₄: 476.3.

Example 6

cis-Ethyl4-(2-(4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 6 steps from cis-ethyl4-aminocyclohexanecarboxylate using a method analogous to thepreparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate.MS m/z=440.2 [M+H]. Calc'd for C₂₄H₂₆FN₃O₄: 439.2.

Example 7

cis-Ethyl4-((E)-2-(benzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 6 steps from cis-ethyl4-aminocyclohexanecarboxylate using a method analogous to thepreparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate.MS m/z=422.2 [M+H]. Calc'd for C₂₄H₂₇N₃O₄: 421.2.

Example 8

cis-Ethyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(40 mg, 57.8% yield). MS m/z=507.2 [M+H]. Calc'd for C₂₉H₃₅FN₄O₃: 506.3.¹H NMR (400 MHz, CDCl₃) δ ppm 1.35 (t, 3H) 1.42-1.51 (m, 2H) 1.52-1.69(m, 5H) 1.71-1.94 (m, 4H) 2.30-2.51 (m, 6H) 2.56-2.75 (m, 2H) 2.77-2.91(m, 1H) 3.51-3.64 (m, 1H) 4.32 (q, J=7.17 Hz, 2H) 4.70-4.90 (m, 1H)7.08-7.16 (m, 2H) 7.18-7.26 (m, 2H) 7.35-7.44 (m, 1H) 8.13-8.55 (m, 2H)12.54 (s, 1H).

Example 9

cis-Ethyl4-((E)-2-(benzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-((E)-2-(benzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(80 mg, 69% yield). MS m/z=489.2 [M+H]. Calc'd for C₂₉H₃₆N₄O₃: 488.3.

Example 10

cis-4-(2-(4-Fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid hydrochloride

A round bottom flask under nitrogen atmosphere was charged withcis-methyl4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.10 g, 0.203 mmol), MeOH (2.90 mL) and 1N aqueous NaOH (3.05 mL, 3.05mmol) and stirred at RT ovenight. The reaction mixture was adjusted to apH of approximately 2 by treatment with 6N HCl and was extracted withDCM (3×50 mL). The organic layers were combined, dried over sodiumsulfate and concentrated under vacuum to afford an off-white solid.Trituration with ether affordedcis-4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid hydrochloride as a white solid (0.095 g, 91% yield). MS m/z=479.2[M+H]. Calc'd for C₂₇H₃₁N₄O₃: 478.2.

Example 11

(E)-N-(1-(cis-4-(Ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (0.025 g, 0.052 mmol) was cooled to 0° C. under nitrogen. To thismixture was added thionyl chloride (0.381 mL, 5.22 mmol), and theresulting reaction mixture was stirred for 10 minutes. The mixture wasconcentrated under reduced pressure and dried under high vacuum. Theresidue was suspended in THF (0.5 mL) and cooled to 0° C. under anitrogen atmosphere. To this mixture was added ethanamine (2M in THF)(0.059 mL, 1.045 mmol) dropwise, and the reaction was stirred at 0° C.for 30 minutes. The reaction mixture was diluted with water (10 mL) andDCM (20 mL), and the layers were separated. The organic phase was driedover sodium sulfate, filtered, and solvent was concentrated underreduced pressure to afford(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(0.025 g, 95% yield). MS m/z=506.2 [M+H]. Calc'd for C₂₉H₃₆FN₅O₂: 505.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.19 Hz, 3H) 1.42-1.50 (m,2H) 1.50-1.63 (m, 4H) 1.63-1.89 (m, 4H) 2.14-2.28 (m, 2H) 2.32-2.47 (m,4H) 2.57-2.66 (m, 1H) 2.67-2.89 (m, 2H) 3.21-3.32 (m, 2H) 3.56 (s, 2H)4.77-5.03 (m, 1H) 7.17-7.23 (m, 1H) 7.25-7.35 (m, 2H) 7.53 (d, J=8.12Hz, 1H) 7.63 (s, 1H) 7.83-7.94 (m, 1H) 8.29-8.43 (m, 2H) 12.79 (s, 1H).

Example 12

cis-Methyl4-((E)-6-(hydroxymethyl)-2-(3-(trifluoromethyl)benzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxyl

The title compound was prepared in 2 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(250 mg, 60.4% yield). MS m/z=476.2 [M+H]. Calc'd for C₂₄H₂₄F₃N₃O₄:475.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.89 (m, 4H) 2.22-2.33 (m,2H) 2.54-2.69 (m, 2H) 2.80-2.94 (m, 1H) 3.76 (s, 3H) 4.60 (d, J=5.58 Hz,2H) 4.70-4.88 (m, 1H) 5.27 (t, J=5.58 Hz, 1H) 7.14-7.23 (m, 1H)7.48-7.57 (m, 2H) 7.70-7.79 (m, 1H) 7.86-7.95 (m, 1H) 8.41 (s, 1H)8.49-8.60 (m, 1H) 12.86 (s, 1H).

Example 13

N-(1-adamantyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)benzamide

Step A: N-Adamantyl-2-nitro-5-((triisopropylsilyloxy)methyl)aniline

The title compound was prepared from(3-fluoro-4-nitrobenzyloxy)triisopropylsilane using a method analogousto that used to prepare cis-methyl4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.7 g, 40.5% yield).

Step B: N1-Adamantyl-5-((triisopropylsilyloxy)methyl)benzene-1,2-diamine

The title compound was prepared fromN-adamantyl-2-nitro-5-((triisopropylsilyloxy)methyl)aniline using amethod analogous to that used to prepare cis-methyl4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (869 mg, 100% yield).MS m/z=429.2 [M+H]. Calc'd for C₂₆H₄₄N₂OSi: 428.3.

Step C:N-1-Adamantyl-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-2-amine

The title compound was prepared fromN1-adamantyl-5-((triisopropylsilyloxy)methyl)benzene-1,2-diamine using amethod analogous to that used to prepare cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(984 mg, 100% yield). MS m/z=454.2 [M+H]. Calc'd for C₂₇H₄₃N₃OSi: 453.3.

Step D:N-(1-Adamanty-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 2 steps fromN-1-adamantyl-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-2-amineusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate.The yield was 200 mg (37.7%, 2 steps). MS m/z=402.2 [M+H]. Calc'd forC₂₅H₂₇N₃O₂: 401.2.

Example 14

cis-Methyl4-(6-(piperidin-1-ylmethyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 3 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(148 mg, 47.3% yield). MS m/z=543.2 [M+H]. Calc'd for C₂₉H₃₃F₃N₄O₃:542.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.46 (m, 2H) 1.47-1.61 (m,4H) 1.69-1.89 (m, 4H) 2.21-2.32 (m, 2H) 2.29-2.41 (m, 4H) 2.53-2.63 (m,2H) 2.82-2.96 (m, 1H) 3.52 (s, 2H) 3.77 (s, 3H) 4.69-4.93 (m, 1H)7.13-7.20 (m, 1H) 7.48 (s, 1H) 7.51 (d, J=8.12 Hz, 1H) 7.69-7.78 (m, 1H)7.90 (d, J=7.63 Hz, 1H) 8.42 (s, 1H) 8.55 (d, J=7.53 Hz, 1H) 12.84 (s,1H).

Example 15

(E)-N-(1-(cis-4-(Methylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(23 mg, 90% yield). MS m/z=492.2 [M+H]. Calc'd for C₂₈H₃₄FN₅O₂: 491.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.50 (m, 2H) 1.52-1.62 (m, 4H)1.64-1.74 (m, 2H) 1.71-1.87 (m, 2H) 2.16-2.28 (m, 2H) 2.35-2.47 (m, 4H)2.59-2.66 (m, 1H) 2.77 (d, J=4.60 Hz, 3H) 2.78-2.85 (m, 2H) 3.57 (s, 2H)4.68-5.04 (m, 1H) 7.13-7.24 (m, 1H) 7.25-7.36 (m, 2H) 7.53 (d, J=8.12Hz, 1H) 7.64 (s, 1H) 7.76-7.87 (m, 1H) 8.27-8.41 (m, 2H) 12.80 (s, 1H).

Example 16

(E)-N-(1-Adamantyl-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromN-(1-adamanty-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)benzamide usinga method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(60 mg, 68.2% yield). MS m/z=469.2 [M+H]. Calc'd for C₃₀H₃₆N₄O: 468.3.

Example 17

(E)-3-(N-Allylsulfamoyl)-N-(1-adamantyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps fromN-1-adamantyl-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-2-amineusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate.The yield was 100 mg (21.8%, 2 steps). MS m/z=521.2 [M+H]. Calc'd forC₂₈H₃₂N₄O₄S: 520.2.

Example 18

3-(N-Allylsulfamoyl)-N-(1-adamantyl-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared from(E)-3-(N-allylsulfamoyl)-N-(1-adamantyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(50 mg, 63.3% yield). MS m/z=588.2 [M+H]. Calc'd for C₂₈H₃₂N₄O₄S: 587.3.

Example 19

cis-Methyl4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

cis-Methyl4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.05 g, 0.123 mmol) was suspended in DCM (1.2 mL) and cooled to 0° C.under nitrogen atmosphere. To this mixture was added thionyl chloride(0.292 g, 2.454 mmol), and the mixture was stirred for 30 minutes. Theresulting mixture was concentrated under reduced pressure and driedunder high vacuum. The residue was suspended in 2 mL of DMSO and cooledin an ice bath under nitrogen atmosphere. To this mixture was added2,2,6,6-tetramethylpiperidine (0.173 g, 1.227 mmol) dropwise, and thereaction was stirred in an ice bath for 30 minutes and at RT for another30 minutes. The reaction mixture was diluted with DCM (20 mL) and washedwith water (10 mL). The organic layer was collected, dried over sodiumsulfate, and concentrated under vacuum. The residual yellow oil wastriturated with 10% water/MeOH to afford cis-methyl4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(20 mg, 30.8% yield). MS m/z=531.2 [M+H]. Calc'd for C₃₂H₄₂N₄O₃: 530.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (s, 12H) 1.54-1.73 (m, 6H)1.73-1.99 (m, 4H) 2.25-2.41 (m, 2H) 2.46-2.54 (m, 2H) 2.84-3.02 (m, 1H)3.81 (s, 3H) 3.93 (s, 2H) 4.73-5.08 (m, 1H) 7.25 (d, J=8.31 Hz, 1H)7.39-7.62 (m, 4H) 7.74 (s, 1H) 8.23-8.35 (m, 2H) 12.76 (s, 1H).

Example 20

cis-Methyl4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

Step A: cis-Methyl4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate

The title compound was prepared from 2,4-dichloro-5-nitropyridine usinga method analogous to the preparation of cis-methyl4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate (2.7 g, 98% yield).MS m/z=314.2 [M+H]. Calc'd for C₁₃H₁₆ClN₃O₄: 313.1.

Step B: cis-Methyl4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate

To a nitrogen purged, cooled (0° C.) suspension of2-(piperidin-1-yl)ethanol (0.577 g, 4.46 mmol) in THF was added sodiumhydride (0.196 g of 60% oil dispersion, 4.91 mmol), and the resultingmixture was stirred for 30 minutes. A solution of cis-methyl4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.40 g,4.46 mmol) in THF (14 mL) was added, and the reaction was stirredovernight at RT. The reaction mixture was quenched with water (10 mL)and the product extracted with DCM (30 mL). The organic layer wascollected, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography (10-30%of 90/10/1 DCM/MeOH/NH₄OH in DCM) to afford cis-methyl4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate(0.6 g, 33.1% yield). MS m/z=407.2 [M+H]. Calc'd for C₂₀H₃₀N₄O₅: 406.2.

Step C: cis-Methyl4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylateusing a method analogous to that used to prepare to cis-methyl4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate(398 mg, 100% yield). MS m/z=377.2 [M+H]. Calc'd for C₂₀H₃₂N₄O₃: 376.2.

Step D: cis-Methyl4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylateusing a method analogous to that used to prepare cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(96 mg, 65% yield). MS m/z=506.2 [M+H]. Calc'd for C₂₈H₃₅N₅O₄: 505.3. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.31-1.43 (m, 2H) 1.44-1.56 (m, 4H)1.65-1.85 (m, 4H) 2.17-2.28 (m, 2H) 2.37-2.46 (m, 4H) 2.53-2.61 (m, 2H)2.65 (t, J=5.98 Hz, 2H) 2.79-2.87 (m, 1H) 3.74 (s, 3H) 4.35 (t, J=5.98Hz, 2H) 4.50-4.69 (m, 1H) 6.92 (s, 1H) 7.43-7.51 (m, 2H) 7.51-7.58 (m,1H) 8.12-8.25 (m, 3H) 12.64 (s, 1H).

Example 21

N-(1-(cis-4-(Diethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 5 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(35 mg, last step=62.5% yield). MS m/z=516.2 [M+H]. Calc'd forC₃₁H₄₁N₅O₂: 515.3.

Example 22

N-(1-(cis-4-Carbamoylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 5 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide.MS m/z=460.2 [M+H]. Calc'd for C₂₇H₃₃N₅O₂: 459.3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.28-1.45 (m, 2H) 1.46-1.58 (m, 4H) 1.60-1.82 (m, 4H)2.08-2.25 (m, 2H) 2.29-2.45 (m, 4H) 2.54-2.61 (m, 1H) 2.61-2.87 (m, 2H)3.40-3.56 (m, 2H) 4.56-5.01 (m, 1H) 6.87-6.94 (m, 1H) 7.12-7.22 (m, 1H)7.31-7.41 (m, 1H) 7.43-7.53 (m, 4H) 7.54-7.63 (m, 1H) 7.96-8.52 (m, 2H)12.76 (s, 1H).

Example 23

N-(1-(cis-4-(Ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 5 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide. MS m/z=488.2 [M+H]. Calc'd forC₂₉H₃₇N₅O₂: 487.3.

Example 24

N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 5 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide.MS m/z=502.2 [M+H]. Calc'd for C₃₀H₃₉N₅O₂: 501.3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.55 Hz, 6H) 1.23-1.28 (m, 1H) 1.64-1.76 (m,6H) 1.78-1.86 (m, 2H) 2.07-2.20 (m, 2H) 2.53-2.57 (m, 1H) 2.78-2.98 (m,4H) 3.31-3.44 (m, 2H) 3.97-4.14 (m, 1H) 4.26-4.36 (m, 3H) 4.66-4.77 (m,1H) 7.37-7.42 (m, 1H) 7.44-7.50 (m, 2H) 7.50-7.56 (m, 1H) 7.57-7.62 (m,1H) 7.65-7.74 (m, 1H) 7.90 (s, 1H) 8.22-8.32 (m, 2H) 9.94 (s, 1H).

Example 25

cis-4-((E)-2-(Benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid

To a suspension of cis-methyl4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(0.052 g, 0.103 mmol) in MeOH (1.0 mL) was added 1N aqueous NaOH (1.028mL, 1.028 mmol), and the resulting mixture was stirred at RT for 48hours. The reaction mixture was concentrated under vacuum to remove MeOHand neutralized with 2 N HCl. The product was extracted with DCM (5-20mL) to affordcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid as an off-white solid (50 mg, 99% yield). MS m/z=492.2 [M+H].Calc'd for C₂₇H₃₃N₅O₄: 491.3.

Example 26

cis-4-((E)-2-(Benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid

The title compound was prepared fromcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(25 mg, 99% yield). MS m/z=519.2 [M+H]. Calc'd for C₂₉H₃₈N₆O₃: 518.3.

Example 27

cis-Methyl4-(2-(3-(N-allylsulfamoyl)-4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 2 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(340 mg, 70% yield, 2 steps). MS m/z=545.2 [M+H]. Calc'd forC₂₆H₂₉FN₄O₆S: 544.2.

Example 28

cis-Methyl4-(2-(4-fluoro-3-(N-(3-methoxypropyl)sulfamoyl)benzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared in 2 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(290 mg, 65.1% yield, 2 steps). MS m/z=577.2 [M+H]. Calc'd forC₂₇H₃₃FN₄O₇S: 576.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.28 (m, 2H)1.70-1.86 (m, 4H) 2.21-2.30 (m, 2H) 2.54-2.58 (m, 1H) 2.80-2.91 (m, 1H)3.30 (s, 3H) 3.55-3.66 (m, 2H) 3.76 (s, 3H) 4.54-4.62 (m, 2H) 4.74-4.88(m, 1H) 4.99-5.06 (m, 1H) 5.09-5.20 (m, 1H) 5.26 (t, J=5.04 Hz, 1H)5.62-5.77 (m, 1H) 7.18 (d, J=8.12 Hz, 1H) 7.45-7.55 (m, 3H) 8.22-8.29(m, 1H) 8.48-8.54 (m, 1H) 8.54-8.59 (m, 1H) 12.80 (s, 1H).

Example 29

N-(1-(cis-4-(tert-Butylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide

The title compound was prepared in 5 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide.MS m/z=516.2 [M+H]. Calc'd for C₃₁H₄₁N₅O₂: 515.3.

Example 30

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(40 mg, 73.7% yield). MS m/z=520.2 [M+H]. Calc'd for C₃₀H₃₈FN₅O₂: 519.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.55 Hz, 6H) 1.27-1.34 (m,2H) 1.68-1.79 (m, 4H) 1.81-1.89 (m, 3H) 2.12-2.25 (m, 2H) 2.59-2.64 (m,1H) 2.84-3.03 (m, 4H) 3.33-3.47 (m, 2H) 3.89-4.03 (m, 1H) 4.05-4.19 (m,1H) 4.29-4.44 (m, 2H) 4.63-4.82 (m, 1H) 7.25-7.34 (m, 2H) 7.47-7.53 (m,1H) 7.64 (d, J=8.22 Hz, 1H) 7.76 (d, J=7.73 Hz, 1H) 8.01 (s, 1H)8.32-8.47 (m, 2H) 10.54 (s, 1H).

Example 31

(E)-N-(1-(cis-4-(Cyclopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(45 mg, 83% yield). MS m/z=518.2 [M+H]. Calc'd for C₃₀H₃₆FN₅O₂: 517.3.

Example 32

(E)-N-(1-(cis-4-(Cyclopropylmethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(35 mg, 63% yield). MS m/z=532.2 [M+H]. Calc'd for C₃₁H₃₈FN₅O₂: 531.3.

Example 33

cis-Methyl4-(2-(3-(N-allylsulfamoyl)-4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-(2-(3-(N-allylsulfamoyl)-4-fluorobenzamido)-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(180 mg, 68.5% yield). MS m/z=612.2 [M+H]. Calc'd for C₃₁H₃₈FN₅O₅S:611.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.14 (m, 2H) 1.21-1.31 (m,2H) 1.32-1.44 (m, 4H) 1.54-1.73 (m, 4H) 2.03-2.16 (m, 2H) 2.15-2.27 (m,4H) 2.68-2.79 (m, 1H) 3.37 (s, 2H) 3.40-3.52 (m, 2H) 3.63 (s, 3H)4.62-4.77 (m, 1H) 4.84-4.92 (m, 1H) 4.97-5.06 (m, 1H) 5.49-5.63 (m, 1H)6.97-7.07 (m, 1H) 7.28-7.41 (m, 3H) 8.09-8.15 (m, 1H) 8.34-8.41 (m, 1H)8.40-8.46 (m, 1H) 12.65 (s, 1H).

Example 34

cis-4-(2-(3-(N-Allylsulfamoyl)-4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid

The title compound was prepared from cis-methyl4-(2-(3-(N-allylsulfamoyl)-4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation ofcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-y1)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid (145 mg, 99% yield). MS m/z=598.2 [M+H]. Calc'd for C₃₀H₃₆FN₅O₅S:597.2.

Example 35

(E)-4-Fluoro-N-(1-(cis-4-(isobutylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(30 mg, 63% yield). MS m/z=534.2 [M+H]. Calc'd for C₃₁H₄₀FN₅O₂: 533.3.

Example 36

(E)-4-Fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

A suspension of(E)-4-fluoro-N-(1-(cis-4-formylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(75 mg, 0.162 mmol) in MeOH (3.2 mL) was cooled to 0° C. under nitrogenatmosphere. To this mixture was added isopropylamine (0.208 mL, 2.432mmol) followed by AcOH (0.056 mL, 0.973 mmol). The resulting mixture wasstirred for 15 minutes. Solid sodium cyanoborohydride (15.28 mg, 0.243mmol) was added in one portion, and the resulting mixture was stirredfor 18 hours at RT. The reaction mixture was quenched with water (10mL), and the aqueous layer was extracted with DCM (30 mL). The organiclayer was collected, dried over sodium sulfate, and concentrated todryness under vacuum. The residue was purified by silica gelchromatography (10-30% of 90/10/1 DCM/MeOH/NH₄OH in DCM) to afford(E)-4-fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(10 mg, 12.20% yield). MS m/z=506.2 [M+H]. Calc'd for C₃₀H₄₀FN₅O: 505.3.

Example 37

(E)-4-Fluoro-N-(1-(cis-4-(hydroxymethyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was a byproduct isolated during preparation of(E)-4-fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(20 mg, 26.6% yield). MS m/z=465.2 [M+H]. Calc'd for C₂₇H₃₃FN₄O₂: 464.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.32 (m, 4H) 1.34-1.46 (m, 2H)1.44-1.57 (m, 4H) 1.56-1.70 (m, 1H) 1.78-1.92 (m, 2H) 1.91-2.01 (m, 2H)2.31-2.42 (m, 4H) 3.33-3.38 (m, 2H) 3.53 (s, 2H) 4.53 (t, J=5.18 Hz, 1H)4.69-4.88 (m, 1H) 7.13-7.19 (m, 1H) 7.26-7.34 (m, 2H) 7.49 (d, J=8.12Hz, 1H) 7.55 (s, 1H) 8.19-8.31 (m, 2H) 12.76 (s, 1H).

Example 38

(E)-3-(N-Allylsulfamoyl)-N-(1-(cis-4-carbamoylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(3-(N-allylsulfamoyl)-4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(10 mg, 20.0% yield). MS m/z=597.2 [M+H]. Calc'd for C₃₀H₃₇FN₆O₄S:596.3. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25-1.30 (m, 4H) 1.45-1.54 (m, 2H)1.56-1.69 (m, 5H) 1.76-1.85 (m, 3H) 2.29-2.38 (m, 2H) 2.40-2.50 (m, 2H)2.68-2.77 (m, 1H) 3.02-3.13 (m, 1H) 3.57-3.66 (m, 1H) 3.69-3.79 (m, 2H)4.21-4.41 (m, 1H) 5.01-5.15 (m, 1H) 5.20-5.32 (m, 1H) 5.72-5.92 (m, 1H)6.76-6.87 (m, 1H) 7.19-7.27 (m, 4H) 7.32-7.48 (m, 1H) 8.21 (s, 1H)8.34-8.49 (m, 1H) 8.56-8.74 (m, 1H) 12.84 (s, 1H).

Example 39

(E)-4-Fluoro-N-(6-(piperidin-1-ylmethyl)-1-(cis-4-(2,2,2-trifluoroethylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(15 mg, 42.8% yield). MS m/z=560.2 [M+H]. Calc'd for C₂₉H₃₃F₄N₅O₂:559.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.46 (m, 2H) 1.46-1.60 (m,4H) 1.62-1.72 (m, 2H) 1.74-1.89 (m, 2H) 2.08-2.21 (m, 2H) 2.22-2.44 (m,4H) 2.63-2.83 (m, 3H) 3.50 (s, 2H) 3.92-4.13 (m, 2H) 4.72-4.98 (m, 1H)7.09-7.20 (m, 1H) 7.20-7.33 (m, 2H) 7.43-7.52 (m, 1H) 7.55 (s, 1H)8.22-8.39 (m, 2H) 8.46-8.62 (m, 1H) 12.76 (s, 1H).

Example 40

(E)-4-Fluoro-N-(1-(cis-4-(isopentylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(15 mg, 43.7% yield). MS m/z=548.2 [M+H]. Calc'd for C₃₂H₄₂FN₅O₂: 547.3.

Example 41

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(15 mg, 25.1% yield). MS m/z=522.2 [M+H]. Calc'd for C₂₉H₃₆FN₅O₃: 521.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J=6.55 Hz, 6H) 1.63-1.72 (m,2H) 1.72-1.87 (m, 2H) 2.14-2.27 (m, 2H) 2.37-2.48 (m, 4H) 2.58-2.63 (m,1H) 2.69-2.89 (m, 2H) 3.60 (s, 2H) 3.62-3.74 (m, 4H) 4.01-4.19 (m, 1H)4.82-5.02 (m, 1H) 7.21 (d, J=8.31 Hz, 1H) 7.26-7.35 (m, 2H) 7.55 (d,J=8.12 Hz, 1H) 7.65-7.73 (m, 2H) 8.22-8.49 (m, 2H) 12.80 (s, 1H).

Example 42

cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid

The title compound was prepared in 4 steps from cis-methyl4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation ofcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid. MS m/z=481.2 [M+H]. Calc'd for C₂₆H₂₉FN₄O₄: 480.2.

Example 43

(E)-N-(6-((4-(Aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

Step A: cis-Methyl4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateand tert-butyl piperidin-4-ylmethylcarbamate using a method analogous tothe preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(45 mg, 77% yield). MS m/z=622.2 [M+H]. Calc'd for C₃₄H₄₄FN₅O₅: 621.3.

Step B:cis-4-((E)-6-((4-((tert-Butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid

The title compound was prepared from cis-methyl4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation ofcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid (440 mg, 100% yield). MS m/z=608.2 [M+H]. Calc'd for C₃₃H₄₂FN₅O₅:607.3.

Step C:(E)-N-(6-((4-(Aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

A suspension ofcis-4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (0.57 g, 0.94 mmol) in thionyl chloride (6.85 mL, 94 mmol) undernitrogen atmosphere was stirred for 30 minutes at RT and thenconcentrated to dryness. The residue was suspended in THF (9.4 mL) andcooled in an ice bath under nitrogen atmosphere. To the resultingmixture was added isopropylamine (0.804 mL, 9.38 mmol) as a solution inTHF (1 mL). The ice bath was removed and the mixture was stirred for 1hour at RT. The resulting mixture was diluted with water (10 mL) and theaqueous layer extracted with DCM (30 mL). The organic layer was driedover sodium sulfate and concentrated to dryness under high vacuum toafford a tan solid. The solid was suspended in HCl (4.0M in dioxanes)(23.45 mL, 94 mmol) and stirred for 16 hours. The mixture wasconcentrated, suspended in DCM and washed with aqueous NaHCO₃ solution.The organic portion was collected, dried over sodium sulfate, andconcentrated to dryness under high vacuum to afford a tan solid. Thesolid was purified by silica gel chromatography (1-10% MeOH/DCM (1%NH₄OH)) to afford(E)-N-(6-((4-(aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(0.3 g, 58.3% yield). MS m/z=549.2 [M+H]. Calc'd for C₃₁H₄₁FN₆O₂: 548.3.

Example 44

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylateand 4-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(100 mg, 55.3% yield). MS m/z=524.2 [M+H]. Calc'd for C₂₈H₃₄FN₅O₄:523.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.30 (m, 2H) 1.34-1.45 (m,2H) 1.46-1.60 (m, 4H) 1.66-1.91 (m, 5H) 2.17-2.27 (m, 2H) 2.35-2.49 (m,3H) 2.53-2.62 (m, 2H) 2.78-2.90 (m, 1H) 3.75 (s, 3H) 4.29-4.46 (m, 2H)4.55-4.70 (m, 1H) 6.94 (s, 1H) 7.23-7.36 (m, 2H) 8.19-8.31 (m, 3H) 12.70(s, 1H).

Example 45

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps from cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(15 mg, 25.2% yield). MS m/z=551.2 [M+H]. Calc'd for C₃₀H₃₉FN₆O₃: 550.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.46 Hz, 6H) 1.24-1.35 (m,1H) 1.35-1.48 (m, 2H) 1.48-1.62 (m, 4H) 1.61-1.88 (m, 4H) 2.02-2.25 (m,2H) 2.37-2.53 (m, 4H) 2.64-2.87 (m, 4H) 3.90-4.16 (m, 1H) 4.29-4.50 (m,2H) 4.74-4.95 (m, 1H) 7.08 (s, 1H) 7.23-7.44 (m, 2H) 7.58-7.89 (m, 1H)8.03-8.56 (m, 3H) 12.68 (s, 1H).

Example 46

(E)-4-Fluoro-N-(1-(cis-4-(isopropyl(methyl)carbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(10 mg, 22.4% yield). MS m/z=534.2 [M+H]. Calc'd for C₃₁H₄₀FN₅O₂: 533.3.

Example 47

(E)-4-Fluoro-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(12 mg, 26.3% yield). MS m/z=547.2 [M+H]. Calc'd for C₃₁H₃₉FN₆O₂: 546.3.¹H NMR (400 MHz, MeOH) 6 ppm 1.25-1.38 (m, 1H) 1.49-1.66 (m, 1H)1.76-2.05 (m, 9H) 2.08-2.21 (m, 2H) 2.87-3.00 (m, 2H) 2.99-3.11 (m, 2H)3.17-3.26 (m, 1H) 3.32-3.37 (m, 4H) 3.48-3.66 (m, 2H) 3.84-4.06 (m, 4H)4.49 (s, 2H) 4.89-5.01 (m, 1H) 7.25-7.36 (m, 2H) 7.57-7.65 (m, 1H)7.73-7.81 (m, 1H) 8.13-8.20 (m, 1H) 8.22-8.33 (m, 2H).

Example 48

2-(1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)aceticacid

The title compound was prepared from with(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideusing a method analogous to the preparation of1-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-2-carboxylicacid (20 mg, 18.6% yield, 3 steps). MS m/z=578.2 [M+H]. Calc'd forC₃₂H₄₀FN₅O₄: 577.3.

Example 49

(E)-4-Fluoro-N-(6-(piperidin-1-ylmethyl)-1-(cis-4-(thiazol-2-ylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

A round bottom flask under nitrogen atmosphere was charged withcis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (50 mg, 0.104 mmol), N,N-dimethylpyridin-4-amine (31.9 mg, 0.261mmol), thiazol-2-amine (15.69 mg, 0.157 mmol), and DMF (2 mL). To thismixture was added EDC (40.1 mg, 0.209 mmol), and the reaction wasstirred for 48 hours. The resulting mixture was diluted with water (10mL) and DCM (30 mL). The organic layer was collected, dried over sodiumsulfate and concentrated to afford a brown oil. The residual oil waspurified by HPLC (10-70% ACN/H₂O; 0.1% TFA) to afford(E)-4-fluoro-N-(6-(piperidin-1-ylmethyl)-1-(cis-4-(thiazol-2-ylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(0.027 g, 46.1% yield). MS m/z=561.2 [M+H]. Calc'd for C₃₀H₃₃FN₆O₂S:560.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23-1.36 (m, 1H) 1.36-1.48 (m,2H) 1.50-1.60 (m, 4H) 1.68-1.84 (m, 2H) 1.86-2.01 (m, 2H) 2.26-2.37 (m,2H) 2.40-2.50 (m, 3H) 2.75-2.90 (m, 2H) 2.98-3.10 (m, 1H) 3.63 (s, 2H)4.77-5.08 (m, 1H) 7.18-7.24 (m, 1H) 7.24-7.32 (m, 2H) 7.36 (d, J=3.62Hz, 1H) 7.52-7.59 (m, 2H) 7.66 (s, 1H) 8.30-8.42 (m, 2H) 12.21 (s, 1H)12.83 (s, 1H).

Example 50

1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-2-carboxylicacid hydrochloride

A round bottom flask was charged with(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(0.042 g, 0.093 mmol) and DCM (1 mL). The resulting suspension wascooled to 0° C. under nitrogen atmosphere. To this mixture was addedthionyl chloride (0.110 g, 0.928 mmol), and the resulting mixture wasstirred at RT for 30 minutes. The mixture was concentrated under reducedpressure, and the residue was dissolved in DMSO (2 mL). To this mixturewas added tert-butyl piperidine-2-carboxylate (0.100 g, 0.538 mmol), andthe reaction mixture was stirred for 2 hours. The reaction mixture wasdiluted with water (2 mL) and extracted with DCM (10 mL). The organiclayer was collected and dried over sodium sulfate and concentrated. Theresidue was purified by HPLC (10-70% ACN/Water, 0.1% TFA) to afford thet-butyl ester intermediate. This material was dissolved in HCl (4M indioxanes) (1.160 mL, 4.64 mmol) and stirred for 16 hours. The resultingmixture was concentrated and dried under high vacuum to afford1-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-2-carboxylicacid hydrochloride (0.02 g, 35.9% yield). MS m/z=564.2 [M+H]. Calc'd forC₃₁H₃₈FN₅O₄: 563.3.

Example 51

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-morpholinoethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 3 steps fromcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a method analogous to the preparation of tert-butyl2-(4-((E)-2-(4-fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)acetate(60 mg, 33.9% yield, last step). MS m/z=553.2 [M+H]. Calc'd forC₂₉H₃₇FN₆O₄: 552.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.55 Hz,6H) 1.25-1.35 (m, 1H) 1.59-1.71 (m, 2H) 1.72-1.86 (m, 2H) 2.05-2.21 (m,2H) 2.49-2.55 (m, 4H) 2.66-2.84 (m, 4H) 3.54-3.69 (m, 4H) 3.96-4.12 (m,1H) 4.36-4.54 (m, 2H) 4.77-4.97 (m, 1H) 7.08 (s, 1H) 7.27-7.37 (m, 2H)7.75 (d, J=7.63 Hz, 1H) 8.29 (s, 1H) 8.33-8.43 (m, 2H) 12.75 (s, 1H).

Example 52

1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylicacid hydrochloride

To a cooled (0° C.) suspension of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(0.062 g, 0.137 mmol) in DCM (2 mL) under nitrogen atmosphere was addedthionyl chloride (0.163 g, 1.370 mmol) dropwise via syringe. Thereaction mixture was stirred at RT for 30 minutes and was concentratedunder reduced pressure. The resulting residue was dissolved in DMSO (2mL) and tert-butyl piperidine-4-carboxylate (230 mg, 1.24 mmol) wasadded in one portion. The resulting mixture was stirred for 2 hours atRT. The mixture was diluted with water (10 mL) and extracted with DCM(20 mL). The organic layer was collected, dried over sodium sulfate,concentrated, and purified by HPLC (10-70% ACN/Water, 0.1% TFA) toafford the t-Butyl ester intermediate. This intermediate was suspendedin HCl (4M in dioxanes) (1.028 mL, 4.11 mmol) and stirred for 16 hours.The reaction mixture was concentrated to dryness, and the residue wastriturated with 1 mL of anhydrous dioxane to afford1-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylicacid hydrochloride (0.02 g, 24.32% yield). MS m/z=564.2 [M+H]. Calc'dfor C₃₁H₃₈FN₅O₄: 563.3.

Example 53

(R)-1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-2-carboxylicacid hydrochloride

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideusing a method analogous to the preparation of1-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylicacid hydrochloride (10 mg, 11.9% yield). MS m/z=550.2 [M+H]. Calc'd forC₃₀H₃₆FN₅O₄: 549.3.

Example 54

(S)-1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-2-carboxylicacid hydrochloride

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideusing a method analogous to the preparation of1-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylicacid hydrochloride (23 mg, 27.4% yield). MS m/z=550.2 [M+H]. Calc'd forC₃₀H₃₆FN₅O₄: 549.3.

Example 55

There is no Example that corresponds to Example 55.

Example 56

(R)-tert-Butyl4-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate

Step A: cis-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylicacid hydrochloride

To a suspension of cis-methyl4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (2.51 g,8.00 mmol) in dioxane (10 mL) was added 4N aqueous HCl (52.0 mL, 208mmol), and the resulting mixture was stirred at 60° C. for 3 hours. Themixture was concentrated to dryness to affordcis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride as a yellow solid (2.69 g, 100% yield). MS m/z=300.2[M+H]. Calc'd for C₁₂H₁₄ClN₃O₄: 299.1.

Step B: (R)-tert-Butyl4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate

A suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride (0.5 g, 1.487 mmol) in thionyl chloride (10.86 mL, 149mmol) was heated at 70° C. for 1.5 hours. The mixture was concentratedunder reduced pressure and dried under high vacuum for 1 hour. Theresulting solid was suspended in THF (14.87 mL) and cooled to 0° C.under nitrogen atmosphere. To this mixture was added (R)-tert-butyl3-methylpiperazine-1-carboxylate (0.357 g, 1.785 mmol) as a solution inTHF (5 mL). The ice bath was removed, and the reaction mixture wasstirred overnight at RT. The resulting mixture was diluted with DCM (100mL) and washed with saturated aqueous NaHCO₃ solution (30 mL) and thenwith saturated aqueous ammonium chloride solution (2×). The organicphase was collected, dried over sodium sulfate, and concentrated underreduced pressure to afford (R)-tert-butyl4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylateas a light yellow solid (0.55 g, 77% yield). MS m/z=482.2 [M+H]. Calc'dfor C₂₂H₃₂ClN₅O₅: 481.2.

Step C: (R)-tert-Butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate

To a solution of (R)-tert-butyl4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(0.4 g, 0.830 mmol) in toluene (8.30 mL) was added2-(piperidin-1-yl)ethanol (0.536 g, 4.15 mmol), 18-crown-6 (0.329 g,1.245 mmol), and cesium carbonate (0.811 g, 2.490 mmol). The reactionwas purged with argon and stirred at 75° C. overnight. The mixture wasdiluted with EtOAc to about 50 mL total volume and washed sequentiallywith water (50 mL), brine (50 mL), and aqueous NH₄Cl (2×50 mL). Theorganic layer was dried over sodium sulfate and concentrated to affordan orange residue. The residue was purified by silica gel chromatography(1-5% MeOH/DCM, 1% NH4OH) to afford (R)-tert-butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylateas a tan solid (0.33 g, 69.2% yield). MS m/z=575.4 [M+H]. Calc'd forC₂₉H₄₆N₆O₆: 574.4.

Step D: (R)-tert-Butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate

To a suspension of (R)-tert-butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate(0.2 g, 0.348 mmol) in MeOH (3.48 mL) was added tin(II) chloride (0.264g, 1.392 mmol). The resulting suspension was stirred at 80° C. for 2hours. The mixture was cooled to RT, diluted with EtOAc and washed with1N aqueous NaOH. The organic layer was collected, dried over sodiumsulfate and concentrated to afford (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylateas a tan solid (190 mg, 100%). MS m/z=545.4 [M+H]. Calc'd forC₂₉H₄₈N₆O₄: 544.4.

Step E: (R)-tert-Butyl4-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate

The title compound was prepared from (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylateand 4-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(80 mg, 67.0% yield). MS m/z=692.4 [M+H]. Calc'd for C₃₇H₅₀FN₇O₅: 691.4.

Example 57

(R)-tert-Butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate

The title compound was prepared from (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylateand 4-cyanobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(84 mg, 57.4% yield). MS m/z=699.4 [M+H]. Calc'd for C₃₈H₅₀N₈O₅: 698.4.

Example 58

(E)-4-Cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

A suspension of (R)-tert-butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(0.07 g, 0.100 mmol) in HCl (4M in dioxanes) (1.252 mL, 5.01 mmol) wasstirred at RT for 16 hours. The mixture was concentrated under reducedpressure, and the residue was suspended in DCM (20 mL) and washed withaqueous NaHCO₃ solution (10 mL). The organic layer was collected, driedover sodium sulfate and concentrated to afford a brown solid. Thismaterial was purified by silica gel chromatography to afford(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(10 mg, 16.7% yield). MS m/z=599.4 [M+H]. Calc'd for C₃₃H₄₂N₈O₃: 598.3.

Example 59

(E)-4-Fluoro-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from (R)-tert-butyl4-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylateusing a method analogous to the preparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(30 mg, 50.1% yield). MS m/z=592.2 [M+H]. Calc'd for C₃₂H₄₂FN₇O₃: 591.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23-1.26 (m, 1H) 1.36-1.43 (m, 2H) 1.48(s, 9H) 1.49-1.54 (m, 4H) 1.76-1.86 (m, 2H) 2.40-2.47 (m, 4H) 2.54-2.59(m, 1H) 2.61-2.70 (m, 2H) 2.84-3.08 (m, 2H) 4.09-4.23 (m, 2H) 4.29-4.43(m, 2H) 4.73-4.91 (m, 1H) 7.00 (s, 1H) 7.41-7.48 (m, 2H) 7.49-7.59 (m,1H) 8.15-8.20 (m, 2H) 8.23 (s, 1H) 12.72 (s, 1H).

Example 60

(S)-tert-Butyl4-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-2-methylpiperazine-1-carboxylate

The title compound was prepared in 4 steps from (S)-tert butyl2-methylpiperazine-1-carboxylate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(90 mg, 59.1% yield, last step). MS m/z=692.2 [M+H]. Calc'd forC₃₇H₅₀FN₇O₅: 691.4.

Example 61

(E)-4-Fluoro-N-(1-(cis-4-((S)-3-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from (S)-tert-butyl4-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-2-methylpiperazine-1-carboxylateusing a method analogous to the preparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(30 mg, 50.1% yield). MS m/z=592.2 [M+H]. Calc'd for C₃₂H₄₂FN₇O₃: 591.3.

Example 62

(E)-4-Fluoro-N-(1-(cis-4-((S)-3-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 5 steps from (S)-tert butyl2-methylpiperazine-1-carboxylate using a method analogous to thepreparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.MS m/z=574.2 [M+H]. Calc'd for C₃₂H₄₃N₇O₃: 573.3.

Example 63

(E)-4-Fluoro-N-(1-(trans-4-hydroxy-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A: trans-Ethyl4-(tert-butoxycarbonylamino)-1-hydroxycyclohexanecarboxylate

To dry THF (60 mL) was added diisopropylamine (6.41 mL, 45.7 mmol). Themixture was cooled to −78° C. and n-butyllithium solution (29.9 mL, 47.8mmol of 1.6M solution in hexanes) was added with stirring. The resultingmixture was stirred at −78° C. for 1 hour. A solution of ethyl4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (5.64 g, 20.78 mmol)in dry THF (40 mL) was added dropwise with stirring over 10 minutes viacannula, and the resulting mixture was stirred at −78° C. for 1.5 hours.A stream of dry air was passed through the mixture for 1.5 hours. Thecooling bath was removed, and the mixture was stirred at RT for 60hours. Saturated aqueous Na₂S₂O₃ and EtOAc were then added, and themixture was stirred vigorously for 30 minutes. The organic layer wasseparated, washed with brine, and the solvent was removed. The residuewas purified by silica gel chromatography (50% EtOAc/Hexane) (KMnO₄stain) to afford cis-ethyl4-(tert-butoxycarbonylamino)-1-hydroxycyclohexanecarboxylate (346 mg,5.8%).

Step B: trans-Ethyl4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylate

To trans-ethyl4-(tert-butoxycarbonylamino)-1-hydroxycyclohexanecarboxylate (346 mg,1.20 mmol) was added saturated EtOH/HCl, and the resulting solution wasallowed to stand at RT for 24 hours. The solvent was removed at reducedpressure, and the residue was dried in vacuo to afford the aminehydrochloride (269 mg, 1.20 mmol) as a colourless solid. The aminehydrochloride was suspended in ACN (5 mL) and2,4-dichloro-5-nitropyridine (0.232 g, 1.20 mmol) and DIPEA (0.732 mL,4.21 mmol) were added. The mixture was heated at 70° C. under argon for5 hours and allowed to stand at RT overnight. The solvent was removed atreduced pressure, and the residue was purified by silica gelchromatography (40% EtOAc/Hexane). The desired fractions were collectedand concentrated to afford a residue which was crystallized fromtoluene/hexane to affordtrans-4-(2-chloro-5-nitropyridin-4-ylamino)-1-ethoxycyclohexanecarboxylicacid as yellow needles (289 mg, 69.9%). MS m/z=344.0 [M+H]. Calc'd forC₁₄H₁₈ClN₃O₅: 343.1.

Step C:trans-4-(2-Chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid

To a suspension of trans-ethyl4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylate(220 mg, 0.640 mmol) in dioxane (0.8 mL) was added 4N aqueous HCl (4.16mL, 16.64 mmol), and the resulting reaction mixture was stirred at 60°C. for 3 hours. The mixture was concentrated to affordtrans-4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid hydrochloride as a yellow solid (225 mg, 100% yield). MS m/z=316.0[M+H]. Calc'd for C₁₂H₁₄ClN₃O₅: 315.1.

Step D:trans-4-(2-Chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamide

To a suspension oftrans-4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid hydrochloride (225 mg, 0.639 mmol) in DMF (6.4 mL) was added CDI(207 mg, 1.278 mmol). The resulting mixture was stirred at RT for 1hour. The mixture was cooled to 0° C. and isopropylamine (1.095 mL,12.78 mmol) was added dropwise as a solution in THF (1 mL). The ice bathwas removed and the mixture stirred at RT for 1 hour. The mixture wasdiluted with DCM (20 mL) and washed with aqueous NH₄Cl (10 mL) and brine(10 mL). The organic layer was collected, dried over sodium sulfate, andconcentrated under reduced pressure to affordtrans-4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamideas a yellow solid (0.22 g, 97% yield). MS m/z=357.2 [M+H]. Calc'd forC₁₅H₂₁ClN₄O₄: 356.1.

Step E:trans-1-Hydroxy-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

The title compound was prepared fromtrans-4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamideusing a method analogous to the preparation of (R)-tert-butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylateand isolated as a tan solid (100 mg, 79.0%). MS m/z=450.2 [M+H]. Calc'dfor C₂₂H₃₅N₅O₅: 449.3

Step F:trans-4-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamide

The title compound was prepared fromtrans-1-hydroxy-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamideusing a method analogous to the preparation of (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(70 mg, 75.0% yield). MS m/z=420.2 [M+H]. Calc'd for C₂₂H₃₇N₅O₃: 419.3

Step G:trans-4-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamide

The title compound was prepared fromtrans-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamideand 4-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(10 mg, 10.0% yield). MS m/z=567.2 [M+H]. Calc'd for C₃₀H₃₉FN₆O₄: 566.3

Example 64

(E)-tert-Butyl4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate

Step A: tert-Butyl4-(2-chloro-5-nitropyridin-4-ylamino)piperidine-1-carboxylate

The title compound was prepared from 2,4-dichloro-5-nitropyridine andtert-butyl 4-aminopiperidine-1-carboxylate using a method analogous tothe preparation of cis-methyl4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate (10.2 g, 55.2%yield). MS m/z=357.2 [M+H]. Calc'd for C₁₅H₂₁ClN₄O₄: 356.1.

Step B: tert-Butyl4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)piperidine-1-carboxylate

The title compound was prepared from tert-butyl4-(2-chloro-5-nitropyridin-4-ylamino)piperidine-1-carboxylate using amethod analogous to the preparation of (R)-tert-butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate(3.0 g, 59.5% yield). MS m/z=450.2 [M+H]. Calc'd for C₂₂H₃₅N₅O₅: 449.3

Step C: tert-Butyl4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)piperidine-1-carboxylate

The title compound was prepared from tert-butyl4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)piperidine-1-carboxylateusing a method analogous to the preparation of (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(2.56 g, 91% yield). MS m/z=420.2 [M+H]. Calc'd for C₂₂H₃₇N₅O₃: 419.3

Step D: (E)-tert-Butyl4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate

The title compound was prepared from tert-butyl4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)piperidine-1-carboxylateusing a method analogous to the preparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(2.4 g, 65.5% yield). MS m/z=549.2 [M+H]. Calc'd for C₃₀H₄₀N₆O₄: 548.3.

Example 65

(E)-N-(6-(2-(Piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from (E)-tert-butyl4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylateusing a method analogous to the preparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(1.9 g, 97%). MS m/z=449.2 [M+H]. Calc'd for C₂₅H₃₂N₆O₂: 448.3. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.16-1.29 (m, 2H) 1.31-1.42 (m, 2H) 1.41-1.55(m, 4H) 1.60-1.77 (m, 2H) 2.26-2.37 (m, 1H) 2.37-2.45 (m, 4H) 2.58-2.70(m, 4H) 3.04-3.17 (m, 2H) 4.29-4.39 (m, 2H) 4.72-4.89 (m, 1H) 7.04-7.06(m, 1H) 7.47-7.51 (m, 2H) 7.51-7.54 (m, 1H) 8.19-8.20 (m, 1H) 8.21-8.22(m, 1H) 8.22-8.24 (m, 1H).

Example 66

(E)-N-(1-(1-(Ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

A suspension of(E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.10 g, 0.223 mmol) in DMF (1.12 mL) was cooled to 0° C. under nitrogenatmosphere. To this mixture was added TEA (0.045 g, 0.446 mmol) followedby ethanesulfonyl chloride (0.043 g, 0.334 mmol). The resulting mixturewas stirred for 30 minutes and diluted with water (10 mL) and DCM (20mL). The organic layer was collected and concentrated to yield a brownresidue. The residue was purified by HPLC (10-70% ACN/H₂O; 0.1% TFA) toafford(E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas an off-white solid (15 mg, 12.4%). MS m/z=541.2 [M+H]. Calc'd forC₂₇H₃₆N₆O₄S: 540.3.

Example 67

(E)-N-(1-(1-(N-Methylsulfamoyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideand methylsulfamoyl chloride using a method analogous to the preparationof(E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(15 mg, 12.4% yield). MS m/z=542.2 [M+H]. Calc'd for C₂₆H₃₅N₇O₄S: 541.3

Example 68

(E)-N-(1-(1-Isobutylpiperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

A suspension of(E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.089 g, 0.198 mmol) and potassium carbonate (0.082 g, 0.595 mmol) inDMF (2 mL) was cooled to 0° C. under nitrogen. To this mixture was added1-bromo-2-methylpropane (0.054 g, 0.397 mmol). The ice bath was removed,and the resulting mixture was stirred for 16 hours at RT. The reactionmixture was diluted with water (10 mL) and DCM (30 mL), and the organiclayer was collected, concentrated and purified by silica gelchromatography (5-30% MeOH/DCM) to afford(E)-N-(1-(1-isobutylpiperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas an off-white solid (20 mg, 19.97% yield). MS m/z=505.2 [M+H]. Calc'dfor C₂₉H₄₀N₆O₂: 504.3.

Example 69

(E)-N-(1-(1-(Isopropylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideand 2-propanesulphonyl chloride using a method analogous to thepreparation of(E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(20 mg, 19.0% yield). MS m/z=555.2 [M+H]. Calc'd for C₂₈H₃₈N₆O₄S: 554.3

Example 70

(E)-N-(1-(cis-4-Acetylcyclohexyl)-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide

Step A: tert-Butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate

To a suspension of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid (3 g, 12.33 mmol) in DCM (35 mL) was added CDI (4.00 g, 24.66 mmol)portion-wise. The resulting mixture was stirred for 1 hour, and thenO,N-dimethylhydroxylamine hydrochloride (1.804 g, 18.50 mmol) was added,and the mixture was stirred at RT for 16 hours. Water (30 mL) was added,and the mixture was stirred for 1 hour and then extracted with DCM (50mL). The organic layer was washed with brine (30 mL), dried over sodiumsulfate and concentrated to afford tert-butylcis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (3.3 g, 93% yield).

Step B: tert-Butyl cis-4-acetylcyclohexylcarbamate

A suspension of tert-butylcis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.7 g, 16.41 mmol)in THF (109 mL) was cooled to 0° C. under nitrogen atmosphere. To thiswas added methylmagnesium iodide (3M in ether solution)(10.94 mL, 32.8mmol) dropwise via syringe, and the mixture was stirred at 0° C. for 1hour. The ice bath was removed, and the reaction mixture was stirred for18 hours at RT. The reaction mixture was again cooled to 0° C. undernitrogen atmosphere and quenched with aqueous NH₄Cl (100 mL). DCM (200mL) was added, and the layers were separated. The organic layer waswashed with brine (30 mL), dried over sodium sulfate and concentrated toafford a yellow oil which was purified by silica gel chromatography(5-30% MeOH/DCM) to afford tert-butyl cis-4-acetylcyclohexylcarbamate asan off-white solid (1.8 g, 45.4% yield).

Step C: 1-(cis-4-Aminocyclohexyl)ethanone hydrochloride

A suspension of tert-butyl cis-4-acetylcyclohexylcarbamate (1.8 g, 7.46mmol) in HCl (4M in dioxane) (93 mL, 373 mmol) was stirred at RT for 16hours. The resulting mixture was concentrated to dryness to afford1-(cis-4-aminocyclohexyl)ethanone hydrochloride as a white solid (1.33g, 100% yield).

Step D:1-(cis-4-(5-(Hydroxymethyl)-2-nitrophenylamino)cyclohexyl)ethanone

The title compound was prepared from (3-fluoro-4-nitrophenyl)methanoland 1-(cis-4-aminocyclohexyl)ethanone hydrochloride using a methodanalogous to the preparation of cis-methyl4-(2-nitro-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate(0.7 g, 41.0% yield). MS m/z=293.2 [M+H]. Calc'd for C₁₅H₂₀N₂O₄: 292.1.

Step E:1-(cis-4-(2-Amino-5-(hydroxymethyl)phenylamino)cyclohexyl)ethanone

The title compound was prepared from1-(cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)ethanone usinga method analogous to the preparation of cis-methyl4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (0.14 g, 98.0%yield). MS m/z=263.2 [M+H]. Calc'd for C₁₅H₂₂N₂O₂: 262.2.

Step F:(E)-N-(1-(cis-4-Acetylcyclohexyl)-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide

The title compound was prepared from1-(cis-4-(2-amino-5-(hydroxymethyl)phenylamino)cyclohexyl)ethanone and4-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(0.15 g, 66.7% yield). MS m/z=410.2 [M+H]. Calc'd for C₁₅H₂₀N₂O₄: 409.2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.27 (m, 1H) 1.48-1.66 (m, 2H)1.85-1.95 (m, 2H) 2.06-2.16 (m, 2H) 2.21 (s, 3H) 2.40-2.48 (m, 1H)2.57-2.73 (m, 1H) 4.60 (d, J=5.77 Hz, 2H) 4.73-4.91 (m, 1H) 5.22 (t,J=5.77 Hz, 1H) 7.16-7.22 (m, 1H) 7.32-7.40 (m, 1H) 7.48-7.58 (m, 2H)7.65 (s, 1H) 7.86-7.93 (m, 1H) 8.05-8.10 (m, 1H) 12.82 (s, 1H).

Example 71

(E)-N-(1-(cis-4-Acetylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide

The title compound was prepared from(E)-N-(1-(cis-4-acetylcyclohexyl)-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamideusing a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(65 mg, 35.6%). MS m/z=535.2 [M+H]. Calc'd for C₃₁H₃₉FN₄O₃: 534.3

Example 72

(E)-3-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(1-(isopropylamino)ethyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

(E)-N-(1-(cis-4-acetylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide(0.06 g, 0.112 mmol) was suspended in 0.37 mL of dichloroethane. To thismixture was added propan-2-amine (7.30 mg, 0.123 mmol) followed bysodium triacetoxyborohydride (0.033 g, 0.157 mmol) and AcOH (6.42 μL,0.112 mmol). The resulting mixture was stirred for 6 hours at RT andquenched with 1N aqueous NaOH (5 mL). DCM (20 mL) was added and thelayers were separated. The organic portion was dried over sodium sulfateand concentrated to afford a yellow residue which was purified by silicagel chromatography (5-30% MeOH/DCM) to afford(E)-3-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(1-(isopropylamino)ethyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas an off-white solid (10 mg, 15.42% yield). MS m/z=578.4 [M+H]. Calc'dfor C₃₄H₄₈FN₅O₂: 577.4.

Example 73

(E)-3-Fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

Step A: tert-Butyl cis-4-carbamoylcyclohexylcarbamate

The title compound was prepared fromcis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid using amethod analogous to the preparation of tert-butylcis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (0.86 g, 78% yield).

Step B: cis-4-(3-Methyl-1H-1,2,4-triazol-5-yl)cyclohexanaminehydrochloride

To a suspension of tert-butyl cis-4-carbamoylcyclohexylcarbamate (0.24g, 0.990 mmol) in toluene (0.8 mL) was added N,N-dimethylacetamidedimethyl acetal (2.90 mL, 19.81 mmol), and the resulting mixture wasrefluxed for 16 hours with a Dean-Stark trap attached. The mixture wasallowed to cool, was diluted with EtOAc (30 mL), and was washed withwater (2-10 mL) and then brine (10 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a brownoil. A premixed solution of hydrazine (0.078 mL, 2.476 mmol) and AcOH(8.22 mL, 144 mmol) was added to the residual oil, and the resultingmixture was heated at 90° C. for 3 hours. The mixture was allowed tocool and poured into water (30 mL). The mixture was extracted with EtOAc(50 mL), and the organic layer was separated and washed sequentiallywith water (10 mL), aqueous NaHCO₃ (10 mL), and brine (10 mL), thendried over Na₂SO₄, filtered and concentrated under reduced pressure togive a tan solid. The solid was suspended in HCl (4M in dioxanes) (12.38mL, 49.5 mmol) and stirred at RT for 16 hours. The mixture wasconcentrated to dryness under reduced pressure to affordcis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexanamine hydrochloride as atan solid (0.15 g, 0.692 mmol, 69.9% yield). MS m/z=181.2 [M+H]. Calc'dfor C₉H₁₆N₅: 180.1.

Step C:(3-(cis-4-(3-Methyl-1H-1,2,4-triazol-5-yl)cyclohexylamino)-4-nitrophenyl)methanol

The title compound was prepared from (3-fluoro-4-nitrophenyl)methanoland cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexanamine hydrochlorideusing a method analogous to the preparation of cis-methyl4-(2-nitro-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate(0.12 g, 78.0% yield). MS m/z=332.2 [M+H]. Calc'd for C₁₆H₂₁N₅O₃: 331.2.

Step D:(4-Amino-3-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexylamino)phenyl)methanol

The title compound was prepared from(3-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexylamino)-4-nitrophenyl)methanolusing a method analogous to the preparation of cis-methyl4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (0.10 g, 92.0%yield). MS m/z=302.2 [M+H]. Calc'd for C₁₆H₂₃N₅O: 301.2.

Step E:(E)-3-Fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(4-amino-3-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexylamino)phenyl)methanoland 3-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(45 mg, 27.5% yield). MS m/z=449.2 [M+H]. Calc'd for C₂₄H₂₅FN₆O₂: 448.2.

Compound 74

(E)-3-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-3-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(3-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 2-(piperidin-4-yl)propan-2-ol using a method analogous to thepreparation of cis-methyl4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(22 mg, 41.9% yield). MS m/z=574.2 [M+H]. Calc'd for C₃₂H₄₀FN₇O₂: 573.3.

Compound 75

(E)-N-(1-(1-(2-(Methylamino)acetyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from (E)-tert-butyl2-(4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl(methyl)carbamateusing a method analogous to the preparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(30 mg, 25.9% yield). MS m/z=520.2 [M+H]. Calc'd for C₂₈H₃₇N₇O₃: 519.3.

Example 76

(E)-tert-Butyl2-(4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl(methyl)carbamate

To a cooled (0° C.) solution of2-(tert-butoxycarbonyl(methyl)amino)acetic acid (0.046 g, 0.245 mmol) inDMF (1.12 mL) under nitrogen atmosphere was added EDC (0.047 g, 0.245mmol), HOBT (0.038 g, 0.245 mmol),(E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.1 g, 0.223 mmol), and DIPEA (0.047 mL, 0.268 mmol). The resultingmixture was stirred for 16 hours and was diluted with water (10 mL) andEtOAc (20 mL). The organic layers were separated, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a brown oil.The oil was purified by silica gel chromatography (1-5% MeOH/DCM) toafford (E)-tert-butyl2-(4-(2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl(methyl)carbamate(50 mg, 36.2% yield). MS m/z=620.2 [M+H]. Calc'd for C₃₃H₄₅N₇O₅: 619.4.

Example 77

cis-Ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-hydroxyethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

Step A: cis-Ethyl4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxylate

To a suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid (5g, 16.68 mmol) in toluene (111 mL) was added 2-(benzyloxy)ethanol (7.62g, 50.0 mmol), cesium carbonate (16.31 g, 50.0 mmol), and 18-crown-6(6.61 g, 25.02 mmol). The resulting mixture was purged with argon andstirred at 75° C. overnight. The mixture was allowed to cool to RT anddiluted with EtOAc to about 150 mL total volume and washed sequentiallywith brine (2-150 mL), aqueous NH₄Cl (2-150 mL) and water (150 mL). Theorganic phase was collected, dried over sodium sulfate and concentratedunder reduced pressure. The residue was suspended in EtOH (111 mL) andthionyl chloride (36.5 mL, 500 mmol) was added dropwise via syringe. Thereaction mixture was stirred at RT for 16 hours. The mixture wasconcentrated to ⅓ volume and diluted with DCM (150 mL). The organicportion was washed with aqueous NaHCO₃ (100 mL), dried over sodiumsulfate and concentrated. The residue was purified by silica gelchormatography (10-50% EtOAc/Hexanes) to afford cis-ethyl4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxylate(5.6 g, 76% yield). MS m/z=444.2 [M+H]. Calc'd for C₂₃H₂₉N₃O₆: 443.2.

Step B: cis-Ethyl4-(5-amino-2-(2-(benzyloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxylateusing a method analogous to the preparation of (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(4.4 g, 86.0% yield). MS m/z=414.2 [M+H]. Calc'd for C₂₃H₃₁N₃O₄: 413.2.

Step C: cis-Ethyl4-((E)-6-(2-(benzyloxy)ethoxy)-2-(3-fluorobenzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-(5-amino-2-(2-(benzyloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylateand 3-fluorobenzoyl isothiocyanate using a method analogous to thepreparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(2.5 g, 82% yield). MS m/z=561.2 [M+H]. Calc'd for C₃₁H₃₃FN₄O₅: 560.2.

Step D: cis-Ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-hydroxyethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

A round bottom flask under nitrogen was charged with cis-ethyl4-((E)-6-(2-(benzyloxy)ethoxy)-2-(3-fluorobenzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(2.5 g, 4.46 mmol), 10% Pd/C (0.712 g, 0.669 mmol), EtOH (8.92 mL), andconcentrated HCl (0.372 mL, 4.46 mmol). The reaction mixture was stirredunder an atmosphere of hydrogen for 24 hours. The mixture was dilutedwith EtOH (50 mL) and filtered through Celite® brand filter aid. Thecake was washed with DCM (50 mL), EtOH (50 mL), and MeOH (50 mL), andthe filtrate was concentrated to dryness. The residue was dissolved in2% MeOH/DCM (100 mL) and washed with aqueous NaHCO₃ (50 mL). The organiclayer was dried over sodium sulfate and concentrated under reducedpressure to afford cis-ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-hydroxyethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateas a tan solid (2.1 g, 100% yield). MS m/z=471.2 [M+H]. Calc'd forC₂₄H₂₇FN₄O₅: 470.2.

Example 78

cis-Ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

Step B: cis-Ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-oxoethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-hydroxyethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-oxoethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(1.8 g, 90% yield). MS m/z=469.2 [M+H]. Calc'd for C₂₄H₂₅FN₄O₅: 468.2.

Step B: cis-Ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-oxoethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation of(E)-4-fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.9 g, 35.4% yield). MS m/z=596.2 [M+H]. Calc'd for C₃₂H₄₂FN₅O₅: 595.3.

Example 79

cis-4-((E)-2-(3-Fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid

The title compound was prepared from cis-ethyl4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateusing a method analogous to the preparation ofcis-4-((E)-2-(benzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid (0.65 g, 97% yield). MS m/z=568.2 [M+H]. Calc'd for C₃₀H₃₈FN₅O₅:567.2.

Example 80

(E)-N-(1-(cis-4-(3,3-Difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide

To a suspension ofcis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid (0.05 g, 0.088 mmol) in DMF (1 mL) was added CDI (0.029 g, 0.176mmol), and the resulting mixture was stirred at RT for 1 hour. To thismixture was added 3,3-difluoroazetidine hydrochloride (0.057 g, 0.440mmol), and the mixture was stirred at RT for 1 hour. The mixture wasdiluted with DCM (10 mL) and washed with aqueous NH₄Cl (5 mL) and brine(5 mL). The organic layer was collected, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(5-75% ACN/H₂O; 0.1% TFA) to afford(E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide(35 mg, 61.8% yield). MS m/z=643.2 [M+H]. Calc'd for C₃₃H₄₁F₃N₆O₄:642.3.

Example 81

(E)-3-Fluoro-N-(1-(cis-4-(3-hydroxyazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide(15 mg, 27.3% yield). MS m/z=623.2 [M+H]. Calc'd for C₃₃H₄₃FN₆O₅: 622.3.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (s, 6H) 1.27-1.37 (m, 4H) 1.62-1.75(m, 4H) 1.72-1.87 (m, 2H) 1.95-2.12 (m, 3H) 2.68-2.76 (m, 3H) 2.76-2.88(m, 2H) 3.00-3.13 (m, 2H) 3.69-3.77 (m, 1H) 3.94-4.01 (m, 1H) 4.03-4.09(m, 1H) 4.13-4.25 (m, 1H) 4.38-4.47 (m, 3H) 4.47-4.57 (m, 1H) 4.74-4.98(m, 1H) 5.74 (d, J=6.26 Hz, 1H) 7.13 (s, 1H) 7.38-7.48 (m, 1H) 7.53-7.62(m, 1H) 7.94-8.02 (m, 1H) 8.16 (d, J=7.73 Hz, 1H) 8.31 (s, 1H) 12.78 (s,1H).

Example 82

(E)-4-Fluoro-N-(1-(cis-4-hydroxy-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A: 4-(Benzylamino)cyclohexanone

To a suspension of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) inDCE (200 mL) was added phenylmethanamine (7.34 mL, 67.2 mmol), AcOH(3.67 mL, 64.0 mmol) and sodium triacetoxyborohydride (19.00 g, 90mmol). The reaction was stirred at RT for 16 hours and then the mixturewas diluted with 1N NaOH (100 mL) and DCM (250 mL). The organic layerwas collected, dried over sodium sulfate and concentrated under reducedpressure. The residue was suspended in acetone (66.7 mL) and treatedwith HCl (2N aqueous) (64.0 mL, 128 mmol), and the mixture was stirredat RT for 16 hours. The reaction mixture was concentrated to half itsvolume and diluted with 1 N aqueous NaOH (100 mL) and DCM (300 mL). Thelayers were separated, and the organic portion was dried over sodiumsulfate and concentrated under reduced pressure to afford a white solid.The solid was purified by silica gel chromatography (5-10% MeOH/DCM) toafford 4-(benzylamino)cyclohexanone (9.1 g, 69.9% yield). MS m/z=204.2[M+H]. Calc'd for C₁₃H₁₇NO: 203.1.

Step B: 4-(Benzylamino)-1-hydroxycyclohexanecarbonitrile

A suspension of 4-(benzylamino)cyclohexanone (5.8 g, 28.5 mmol) in ether(112 mL) was cooled to 0° C. To this mixture was added NaCN (1.538 g,31.4 mmol) as a solution in NaHCO₃ (4.79 g, 57.1 mmol) and water (71.4mL, 3966 mmol). The reaction mixture was stirred at RT for 16 hours. Theresulting mixture was diluted with ether (110 mL) and water (50 mL). Thelayers were separated, and the organic portion was dried over sodiumsulfate and concentrated under reduced pressure to afford4-(benzylamino)-1-hydroxycyclohexanecarbonitrile as a light yellow solid(5.6 g, 85% yield). MS m/z=231.2 [M+H]. Calc'd for C₁₄H₁₈N₂O: 230.1.

Step C: 4-(Benzylamino)-1-hydroxycyclohexanecarboxylic acidhydrochloride

A suspension of 4-(benzylamino)-1-hydroxycyclohexanecarbonitrile (6 g,26.1 mmol) in aqueous HCl (10 N) (67.1 mL, 782 mmol) was stirred at 65°C. for 16 hours. The mixture was concentrated under reduced pressure toafford 4-(benzylamino)-1-hydroxycyclohexanecarboxylic acid hydrochlorideas a light yellow solid (7.0 g, 94% yield). MS m/z=250.2 [M+H]. Calc'dfor C₁₄H₁₉NO₃: 249.1.

Step D: 4-Amino-1-hydroxycyclohexanecarboxylic acid hydrochloride

4-(Benzylamino)-1-hydroxycyclohexanecarboxylic acid (0.44 g, 1.765 mmol)and 10% palladium on carbon (0.282 g, 0.265 mmol) were charged into around bottom flask under nitrogen atmosphere. To this was added EtOH(8.82 mL), and the mixture was stirred under an atmosphere of hydrogenat RT for 72 hours. The mixture was diluted with EtOH (10 mL) andfiltered through Celite® brand filter aid, rinsing with DCM (10 mL),EtOH (10 mL), and MeOH (10 mL). The filtrate was concentrated underreduced pressure to afford 4-amino-1-hydroxycyclohexanecarboxylic acidas a yellow solid (0.28 g, 100% yield). MS m/z=160.2 [M+H]. Calc'd forC₇H₁₃NO₃: 159.1.

Step E:4-(2-Chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid

A 100 mL round bottom flask was charged with4-amino-1-hydroxycyclohexanecarboxylic acid hydrochloride (0.28 g, 1.431mmol), potassium carbonate (0.435 g, 3.15 mmol) and water (1.908 mL). Tothe mixture was added 2,4-dichloro-5-nitropyridine (0.276 g, 1.431 mmol)as a solution in dioxane (0.954 mL). After the resulting mixture wasstirred at 60° C. for 24 hours, it was cooled to RT and treated with 2Naqueous HCl to bring the pH to about 4-5. The aqueous layer wasextracted with DCM (3×40 mL). The combined organic portions were driedover sodium sulfate and concentrated to afford4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid as a yellow solid (0.28 g, 62.0% yield). MS m/z=316.2 [M+H]. Calc'dfor C₁₂H₁₄ClN₃O₅: 315.1.

Step F:4-(2-Chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-methylcyclohexanecarboxamide

The title compound was prepared from4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylicacid using a method analogous to that used for the synthesis ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-isopropylcyclohexanecarboxamide(240 mg, 82% yield). MS m/z=329.2 [M+H]. Calc'd for C₁₃H₁₇ClN₄O₄: 328.1.

Step G:1-Hydroxy-N-methyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

The title compound was prepared from4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxy-N-methylcyclohexanecarboxamideusing a method analogous to the preparation of (R)-tert-butyl3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate(150 mg, 49.8% yield). MS m/z=422.2 [M+H]. Calc'd for C₂₀H₃₁N₅O₅: 421.2.

Step H:4-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-hydroxy-N-methylcyclohexanecarboxamide

The title compound was prepared from1-hydroxy-N-methyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamideusing a method analogous to the preparation of (R)-tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate(46 mg, 100% yield). MS m/z=392.2 [M+H]. Calc'd for C₂₀H₃₃N₅O₃: 391.3.

Step I:(E)-4-Fluoro-N-(1-(cis-4-hydroxy-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared from4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-hydroxy-N-methylcyclohexanecarboxamideusing a method analogous to the preparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate(10 mg, 18.2% yield). MS m/z=539.2 [M+H]. Calc'd for C₂₈H₃₅FN₆O₄: 538.3.

Example 83

(E)-4-Fluoro-N-(1-(trans-4-hydroxy-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was isolated from the reaction to prepare(E)-4-fluoro-N-(1-(cis-4-hydroxy-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(8 mg, 14.5% yield). MS m/z=539.2 [M+H]. Calc'd for C₂₈H₃₅FN₆O₄: 538.3.

Example 84

(E)-N-(1-(cis-4-(cis-2,5-Diazabicyclo[2.2.1]heptane-2-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide

Intermediate cis-tert-butyl5-(cis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylatewas prepared fromcis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylicacid using a method analogous to the preparation of(E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide.The unpurified intermediate compound was deprotected using a procedureanalogous to that used in the preparation of(E)-4-cyano-N-(1-(cis-4-((R)-2-methylpiperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideto afford the title compound (10 mg, 17.5% yield). MS m/z=648.2 [M+H].Calc'd for C₃₅H₄₆FN₇O₄: 647.4.

Example 85

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateand morpholine using a method analogous to the preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(20 mg, 31.3% yield). MS m/z=495.2 [M+H]. Calc'd for C₂₇H₃₁FN₄O₄: 494.2.

3-Fluorobenzoyl isothiocyanate

Potassium thiocyanate (11.03 g, 114 mmol) was suspended in acetone (63.1mL) and heated to 40° C. under nitrogen atmosphere. To this was added3-fluorobenzoyl chloride (11.35 mL, 95 mmol), and the resulting mixturewas stirred at 50° C. for 6 hours. The heterogeneous mixture wasfiltered, and the solid was further washed with acetone. The filtratewas concentrated and purified by silica gel chromatography (10%EtOAc/Hexanes as the eluent) to afford 3-fluorobenzoyl isothiocyanate(6.5 g, 37.9% yield) as a light orange oil.

4-Cyanobenzoyl isothiocyanate

The title compound was prepared from 4-cyanobenzoyl chloride using amethod analogous to that used in the preparation of 3-fluorobenzoylisothiocyanate (1.0 g, 16.0% yield).

4-Fluorobenzoyl isothiocyanate

The title compound was prepared from 4-fluorobenzoyl chloride using amethod analogous to that used in the preparation of 3-fluorobenzoylisothiocyanate (11.1 g, 44% yield).

3-(N-allylsulfamoyl)benzoic acid

To a solution of 3-(chlorosulfonyl)benzoic acid (5 g, 22.66 mmol) in THF(50.4 mL) at 0° C. was added allylamine (2.038 mL, 27.2 mmol) followedby NaOH (1N aqueous) (49.9 mL, 49.9 mmol). The mixture was allowed towarm to RT over 1 hour and stirred an additional 16 hours. The mixturewas diluted with 1N HCl (250 mL), and the aqeuous layer was extractedwith EtOAc (300 mL). The organic layer was dried over sodium sulfate andconcentrated to dryness to afford 3-(N-allylsulfamoyl)benzoic acid aswhite solid (5.2 g, 95% yield). MS m/z=242.0 [M+H]. Calc'd forC₁₀H₁₁NO₄S: 241.0.

2-Fluoro-5-(N-(3-methoxypropyl)sulfamoyl)benzoic acid

The title compound was prepared from 5-(chlorosulfonyl)-2-fluorobenzoicacid using a method analogous to the preparation of3-(N-allylsulfamoyl)benzoic acid (1.0 g, 82% yield). MS m/z=292.0 [M+H].Calc'd for C₁₁H₁₄FNO₅S: 291.1.

5-(N-allylsulfamoyl)-2-fluorobenzoic acid

The title compound was prepared from 5-(chlorosulfonyl)-2-fluorobenzoicacid using a method analogous to the preparation of3-(N-allylsulfamoyl)benzoic acid (0.8 g, 73.7% yield). MS m/z=260.0[M+H]. Calc'd for C₁₀H₁₀FNO₄S: 259.0.

cis-Ethyl 4-aminocyclohexanecarboxylate

The title compound was prepared from cis-4-aminocyclohexanecarboxylicacid using a method analogous to cis-methyl4-aminocyclohexanecarboxylate.

Example 86

cis-4-(2-Amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide

Step A:cis-4-(2-Chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamidehydrochloride (12.58 g, 57.0 mmol) and DIPEA (29.0 mL, 166 mmol) in ACN(104 mL) was added 2,4-dichloro-5-nitropyridine (10.00 g, 51.8 mmol).The resulting mixture was stirred at RT for 24 hours. The reactionmixture was diluted with water and washed with DCM (×2). The combinedorganic layers were washed with a minimal volume of brine, dried oversodium sulfate, filtered and concentrated in vacuo. After almostcomplete concentration of solvent, EtOAc was added, and the solidprecipitate was collected yieldingcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideas a yellow solid (12.97 g, 73.4% yield).

Step B:cis-N-Isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

A round-bottom flask under nitrogen was charged with 1-piperidineethanol(19.34 mL, 147 mmol), 18-crown-6 (11.63 g, 44.0 mmol),cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(10.00 g, 29.3 mmol), cesium carbonate (28.7 g, 88 mmol) and toluene(196 mL). The reaction mixture was purged with nitrogen and heated at75° C. for 12 hours. The reaction mixture was diluted with EtOAc, andwashed with brine, followed by saturated NH₄Cl (aq). The aqueous layerswere back-extracted with EtOAc, and the combined organic layers weredried over magnesium sulfate, filtered and concentrated in vacuo. Theresidual material was purified via silica gel chromatography elutingwith isocratic 90:10:1 DCM:MeOH:NH₄OH, to providecis-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide(10.79 g, 85% yield) as a rust-colored solid, which was taken forwardwithout further purification. MS m/z=434.2 [M+H], calc 433.54 forC₂₂H₃₅N₅O₄.

Step C:cis-4-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide(10.79 g, 24.89 mmol) in MeOH (124 mL) was added tin (II) chloride(18.88 g, 100 mmol), and the reaction was stirred at 80° C. for 2 hours.The reaction mixture was concentrated in vacuo, and the residue wasdissolved in EtOAc, then diluted with 1N aqueous NaOH. The layers wereseparated, and the organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo to yieldcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(8.06 g, 80% yield). MS m/z=404.2 [M+H], calc 403.56 for C₂₂H₃₇N₅O₂.

Step D:cis-4-(2-Acetamido-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide

Acetyl isothiocyanate (1.755 mL, 19.97 mmol) was added to a heated (100°C. oil bath) solution ofcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarbox-amide(8.06 g, 19.97 mmol) in dioxane (100 mL). After 5 minutes, completeconversion to the thiourea intermediate was observed. The reaction wascooled to RT, and EDC (11.49 g, 59.9 mmol) and DIPEA (12.56 mL, 71.9mmol) were added. Heating was resumed at 60° C. for 2.5 hours. Thereaction mixture was pre-absorbed onto silica gel, and purified viasilica gel chromatography, eluting with 90:10:1 DCM:MeOH:NH₄OH to yieldcis-4-(2-acetamido-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(8.56 g, 18.19 mmol, 91% yield) as an orange solid. MS m/z=471.2 [M+H],calc 470.61 for C₂₅H₃₈N₆O₃.

Step E:cis-4-(2-Amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide

cis-4-(2-Acetamido-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(8.56 g, 18.19 mmol) was diluted with 2N HCl (aq) (91 mL, 182 mmol) andheated at 50° C. overnight. The reaction mixture was concentrated invacuo, and purified via silica gel chromatography using 0-100% 90:10:1DCM:MeOH:NH₄OH in DCM to yieldcis-4-(2-amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(6.39 g, 82% yield). MS m/z=429.2 [M+H], calc 428.57 for C₂₃H₃₆N₆O₂.

Example 87

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide

1-Benzothiophene-5-carboxylic acid (0.022 g, 0.124 mmol), EDC (0.036 g,0.186 mmol) and HOBT (0.019 g, 0.124 mmol) were combined in DMF (0.124mL). A solution ofcis-4-(2-amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(0.053 g, 0.124 mmol) in DMF (0.124 mL) was added, followed by DIPEA(0.086 mL, 0.495 mmol). The reaction mixture was stirred at RT for 16 h.The mixture was diluted with EtOAc and washed with water (×1) and brine(×1). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residual material was purified via silica gelchromatography, eluting with a gradient of 0% to 100% 90:10:1DCM:MeOH:NH₄OH in DCM to provide a residual material, which was furtherpurified via reverse-phase preparative HPLC (0.1% TFA in ACN/H₂O,gradient 10% to 90% over 20 min) to provide the TFA salt of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo-[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamideas a white solid (0.020 g, 23.01% yield). MS m/z=589.2 [M+H], calc588.76 for C₃₂H₄₀N₆O₃S.

Example 88

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)thiazole-5-carboxamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using thiazole-5-carboxylic acid. After preparative HPLC purification inthe last step, the TFA salt was free-based using an SCX-ion exchangecolumn to obtain(Z)—N—((R)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-5-(2-(piperidin-1-yl)ethoxy)-1H-pyrrolo[2,3-c]pyridin-2(3H)-ylidene)thiazole-5-carboxamideas a white solid (20.68% yield). MS m/z=540.2 [M+H], calc 539.69 forC₂₇H₃₇N₇O₃S. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J=6.55 Hz, 6H)1.32-1.42 (m, 2H) 1.44-1.55 (m, 4H) 1.55-1.76 (m, 4H) 2.01-2.13 (m, 2H)2.37-2.48 (m, 4H) 2.58-2.72 (m, 6H) 4.01 (dq, J=13.77, 6.99 Hz, 1H) 4.35(t, J=6.06 Hz, 2H) 4.65-4.83 (m, 1H) 7.67 (d, J=7.24 Hz, 1H) 8.23 (s,1H) 8.53 (s, 1H) 9.18 (s, 1H) 12.56 (br. s., 1H).

Example 89

(E)-4-Cyano-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-cyanobenzoic acid. After preparative HPLC purification, the TFAsalt was free-based using an SCX-ion exchange column to obtain(E)-4-cyano-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas a light yellow solid (34.6% yield). MS m/z=558.2 [M+H], calc 557.69for C₃₁H₃₉N₇O₃.

Example 90

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)isonicotinamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using isonicotinic acid. After preparative HPLC purification, the TFAsalt was free-based using an SCX-ion exchange column to obtain(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)isonicotinamideas a tan solid (44.2% yield). MS m/z=534.2 [M+H], calc 533.67 forC₂₉H₃₉N₇O₃.

Example 91

(E)-3-Cyano-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-cyanobenzoic acid (35% yield; white solid). MS m/z=558.2 [M+H],calc 557.69 for C₃₁H₃₉N₇O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22 (d,J=6.55 Hz, 6H) 1.37-1.56 (m, 1H) 1.75-2.11 (m, 9H) 2.18-2.27 (m, 2H)2.51-2.56 (m, 1H) 2.73-2.98 (m, 4H) 3.52-3.58 (m, 2H) 3.75-3.85 (m, 2H)4.11-4.21 (m, 1H) 4.75-4.81 (m, 2H) 4.85-4.96 (m, 1H) 5.40-5.46 (m, 1H)7.31 (s, 1H) 7.61 (t, J=7.9 Hz, 1H) 7.80 (dt, J=7.68, 1.39 Hz, 1H) 8.17(s, 1H) 8.53 (dt, J=7.95, 1.41 Hz, 1H) 8.63-8.66 (m, 1H) 11.49 (br. s.,1H).

Example 92

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-(trifluoromethyl)benzoic acid (32.3% yield; white solid). MSm/z=601.2 [M+H], calc 600.67 for C₃₁H₃₉F₃N₆O₃.

Example 93

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(methylsulfonyl)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-(methylsulfonyl)benzoic acid (50.7% yield; white solid). MSm/z=611.4 [M+H], calc 610.77 for C₃₁H₄₂N₆O₅S.

Example 94

(E)-2,4-Difluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 2,4-difluorobenzoic acid (14.5% yield; white solid). MS m/z=569.2[M+H], calc 568.66 for C₃₀H₃₈F₂N₆O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.20(d, J=6.46 Hz, 6H) 1.35-1.52 (m, 2H) 1.72-1.85 (m, 4H) 1.85-1.97 (m, 3H)1.96-2.12 (m, 2H) 2.13-2.21 (m, 2H) 2.45-2.51 (m, 1H) 2.64-2.82 (m, 2H)2.83-94 (m, 2H) 3.49-3.61 (m, 2H) 3.75-3.80 (m, 2H) 4.05-4.19 (m, 1H)4.71-4.91 (m, 3H) 5.43-5.47 (m, 1H) 6.82-6.91 (m, 1H) 6.93-6.98 (m, 1H)8.12-8.28 (m, 2H) 11.79 (br. s., 1H).

Example 95

(E)-4-Bromo-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-bromobenzoic acid (22.4% yield; white solid). MS m/z=612.2[M+H], calc 611.57 for C₃₀H₃₉BrN₆O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.21(d, J=6.55 Hz, 6H) 1.33-1.55 (m, 1H) 1.73-2.27 (m, 11H) 2.48-2.54 (m,1H) 2.67-2.99 (m, 4H) 3.51-3.59 (m, 2H) 3.74-3.82 (d, 2H) 4.10-4.20 (m,1H) 4.75-4.90 (m, 3H) 5.39-5.44 (m, 1H) 7.30 (s, 1H) 7.45-7.73 (m, 2H)7.97-8.33 (m, 3H) 11.52 (br. s., 1H)

Example 96

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)nicotinamide

The TFA salt of the compound was prepared using a method analogous tothe preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using nicotinic acid (60.9% yield; white solid). MS m/z=534.2 [M+H],calc 533.67 for C₂₉H₃₉N₇O₃.

Example 97

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)pyridazine-4-carboxamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using pyridazine-4-carboxylic acid (32.4% yield; yellow solid). MSm/z=535.2 [M+H], calc 534.65 for C₂₈H₃₈N₈O₃. ¹H NMR (400 MHz, CDCl₃) δppm 1.22 (d, J=6.55 Hz, 6H) 1.38-1.54 (m, 1H) 1.76-1.97 (m, 7H)2.04-2.26 (m, 4H) 2.52-2.56 (m, 1H) 2.77-2.95 (m, 4H) 3.48-3.55 (m, 2H)3.75-3.82 (m, 2H) 4.11-4.23 (m, 1H) 4.77-4.91 (m, 3H) 5.40-5.45 (m, 1H)7.23 (s, 1H) 8.23 (s, 1H) 8.56 (dd, J=5.04, 2.01 Hz, 1H) 9.47 (dd,J=5.28, 1.17 Hz, 1H) 10.09 (dd, J=1.96, 1.17 Hz, 1H) 11.73 (br. s., 1H).

Example 98

(E)-3,5-Difluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3,5-difluorobenzoic acid (50.8% yield; white solid). MS m/z=569.2[M+H], calc 568.66 for C₃₀H₃₈F₂N₆O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22(d, J=6.55 Hz, 6H) 1.38-1.54 (m, 1H) 1.74-2.25 (m, 11H) 2.48-2.57 (m,1H) 2.70-2.97 (m, 4H) 3.52-3.59 (m, 2H) 3.74-3.84 (m, 2H) 4.10-4.21 (m,1H) 4.78-4.83 (m, 2H) 4.83-4.96 (m, 1H) 5.40-5.45 (m, 1H) 6.93-7.02 (m,1H) 7.33 (s, 1H) 7.83 (dd, J=8.17, 2.30 Hz, 2H) 8.18 (s, 1H) 11.44 (br.s., 1H)

Example 99

(E)-3-(N-Allylsulfamoyl)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-(N-allylsulfamoyl)benzoic acid (27.4% yield; white solid). MSm/z=652.2 [M+H], calc 651.82 for C₃₃H₄₅N₇O₅S.

Example 100

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-methoxybenzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-methoxybenzoic acid (38.0% yield; white solid). MS m/z=563.2[M+H], calc 562.70 for C₃₁H₄₂N₆O₄. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09(d, J=6.55 Hz, 6H) 1.30-1.51 (m, 1H) 1.56-1.91 (m, 9H) 2.01-2.10 (m, 2H)2.56-2.73 (m, 2H) 2.94-3.11 (m, 2H) 3.47-3.60 (m, 4H) 3.83 (s, 3H)3.90-4.01 (m, 2H) 4.61-4.67 (m, 2H) 6.98-7.01 (m, 2H) 7.09 (s, 1H) 7.74(d, J=7.82 Hz, 1H) 8.19 (d, J=8.71 Hz, 2H) 8.26 (s, 1H) 9.31 (br. s.,1H) 12.55 (br. s., 1H).

Example 101

(E)-3-Chloro-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-chloro-4-fluorobenzoic acid (44.7% yield; white solid). MSm/z=585.2 [M+H], calc 585.11 for C₃₀H₃₈ClFN₆O₃. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.22 (d, J=6.6 Hz, 6H) 1.40-1.53 (m, 1H) 1.74-2.13 (m, 9H)2.15-2.26 (m, 2H) 2.48-2.55 (m, 1H) 2.72-2.96 (m, 4H) 3.51-3.57 (m, 2H)3.74-3.83 (m, 2H) 4.10-4.22 (m, 1H) 4.75-4.81 (m, 2H) 4.81-4.92 (m, 1H)5.38-5.44 (m, 1H) 7.22 (t, J=8.61 Hz, 1H) 7.30 (s, 1H) 8.16 (s, 1H) 8.23(ddd, J=8.6, 4.9, 2.2 Hz, 1H) 8.36 (dd, J=7.29, 2.10 Hz, 1H) 11.46 (br.s., 1H).

Example 102

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-(trifluoromethyl)benzoic acid (48.0% yield; white solid). MSm/z=601.2 [M+H], calc 600.67 for C₃₁H₃₉F₃N₆O₃. ¹H NMR (400 MHz, CDCl₃) δppm 1.21 (d, J=6.6 Hz, 6H) 1.35-1.57 (m, 1H) 1.76-2.29 (m, 11H)2.49-2.56 (m, 1H) 2.73-2.98 (m, 4H) 3.51-3.60 (m, 2H) 3.73-3.84 (m, 2H)4.09-4.21 (m, 1H) 4.75-4.96 (m, 3H) 5.39-5.46 (m, 1H) 7.31 (s, 1H) 7.73(d, J=8.4 Hz, 2H) 8.18 (s, 1H) 8.42 (d, J=8.0 Hz, 2H) 11.49 (br. s.,1H).

Example 103

(E)-4-Cyano-3-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-y1)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-cyano-3-fluorobenzoic acid (40.4% yield; white solid). MSm/z=576.2 [M+H], calc 575.68 for C₃₁H₃₈FN₇O₃.

Example 104

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-1H-indole-6-carboxamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using indole-6-carboxylic acid (6.9% yield; off-white solid). MSm/z=572.2 [M+H], calc 571.71 for C₃₂H₄₁N₇O₃.

Example 105

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(methylamino)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-(methylamino)benzoic acid (26.6% yield; off-white solid). MSm/z=562.2 [M+H], calc 561.72 for C₃₁H₄₃N₇O₃.

Example 106

(E)-2-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)isonicotinamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 2-fluoroisonicotinic acid (6.4% yield; white solid). MS m/z=552.2[M+H], calc 551.66 for C₂₉H₃₈FN₇O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.21(d, J=6.6 Hz, 6H) 1.38-1.54 (m, 1H) 1.73-2.11 (m, 9H) 2.16-2.27 (m, 2H)2.49-2.57 (m, 1H) 2.75-2.97 (m, 4H) 3.52-3.59 (m, 2H) 3.75-3.87 (m, 2H)4.10-4.21 (m, 1H) 4.76-4.89 (m, 3H) 5.40-5.49 (m, 1H) 7.31 (s, 1H) 7.80(s, 1H) 8.03 (dt, J=5.06, 1.53 Hz, 1H) 8.21 (s, 1H) 8.37 (d, J=5.18 Hz,1H) 11.05 (br. s., 1H).

Example 107

(E)-3,4-Difluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3,4-difluorobenzoic acid (36.4% yield; white solid). MS m/z=569.2[M+H], calc 568.66 for C₃₀H₃₈F₂N₆O₃.

Example 108

(E)-3-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-fluorobenzoic acid (53.5% yield; white solid). MS m/z=551.2[M+H], calc 550.67 for C₃₀H₃₉FN₆O₃. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.21(d, J=6.6 Hz, 6H) 1.33-1.56 (m, 1H) 1.75-2.11 (m, 9H) 2.15-2.26 (m, 2H)2.46-2.56 (m, 1H) 2.65-2.99 (m, 4H) 3.48-3.59 (m, 2H) 3.75-3.82 (m, 2H)4.08-4.23 (m, 1H) 4.75-4.80 (m, 2H) 4.83-4.97 (m, 1H) 5.36-5.46 (m, 1H)7.20-7.26 (m, 1H) 7.28 (s, 1H) 7.45 (td, J=7.97, 5.58 Hz, 1H) 8.00 (ddd,J=9.85, 2.57, 1.47 Hz, 1H) 8.09 (dt, J=7.82, 1.17 Hz, 1H) 8.16 (d,J=0.59 Hz, 1H) 11.68 (br. s., 1H).

Example 109

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-1-methyl-1H-indole-6-carboxamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 1-methyl-1H-indole-6-carboxylic acid (33.7% yield; white solid).MS m/z=586.2 [M+H], calc 585.74 for C₃₃H₄₃N₇O₃. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.6 Hz, 6H) 1.27-1.53 (m, 1H) 1.61-1.79 (m,7H) 1.79-1.91 (m, 2H) 1.96-2.14 (m, 2H) 2.56-2.74 (m, 3H) 2.93-3.13 (m,2H) 3.46-3.60 (m, 4H) 3.85-4.02 (m, 5H) 4.60-4.69 (m, 2H) 6.50 (dd,J=3.1, 0.7 Hz, 1H) 7.12 (s, 1H) 7.52 (d, J=3.1 Hz, 1H) 7.61 (d, J=8.3Hz, 1H) 7.74 (d, J=7.4 Hz, 1H) 7.95 (br. s., 1H) 8.27-8.35 (m, 2H) 9.30(br. s., 1H).

Example 110

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)picolinamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using picolinic acid (45.7% yield; white solid). MS m/z=534.2 [M+H],calc 533.67 for C₂₉H₃₉N₇O₃.

Example 111

(E)-3-Cyano-5-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-y1)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-cyano-5-fluorobenzoic acid (9.94% yield; white solid). MSm/z=576.2 [M+H], calc 575.68 for C₃₁H₃₈FN₇O₃.

Example 112

cis-4-((E)-2-(Cyclohexanecarbonylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide

The TFA salt of the title compound was prepared using a method analogousto the preparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using cyclohexanecarboxylic acid (52.5% yield; colorless oil). MSm/z=539.2 [M+H], calc 538.72 for C₃₀H₄₆N₆O₃.

Example 113

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxybenzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-y1)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-fluoro-3-methoxybenzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxybenzamide(43.1% yield). MS m/z=581.4 [M+H], calc 580.69 for C₃₁H₄₁FN₆O₄.

Example 114

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethyl)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-fluoro-3-(trifluoromethyl)benzoic acid. The material waspurified via preparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethyl)benzamide(43.8% yield). MS m/z=619.4 [M+H], calc 618.67 for C₃₁H₃₈F₄N₆O₃—

Example 115

(E)-3-Chloro-5-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-chloro-5-fluorobenzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-3-chloro-5-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(38.5% yield). MS m/z=585.4 [M+H], calc 585.11 for C₃₀H₃₈ClFN₆O₃.

Example 116

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxybenzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-methoxybenzoic acid. The material was purified via preparativeHPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-methoxy-benzamide(42.5% yield). MS m/z=563.4 [M+H], calc 562.71 for C₃₁H₄₂N₆O₄.

Example 117

(E)-3-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-5-methoxybenzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-fluoro-5-methoxybenzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-3-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]-pyridin-2(3H)-ylidene)-5-methoxybenzamide(43.8% yield). MS m/z=581.4 [M+H], calc 580.69 for C₃₁H₄₁FN₆O₄.

Example 118

(E)-3-Chloro-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-chloro-4-fluorobenzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-3-chloro-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(45.4% yield). MS m/z=585.4 [M+H], calc 585.12 for C₃₀H₃₈ClFN₆O₃.

Example 119

(E)-3-Chloro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-chlorobenzoic acid. The material was purified via preparativeHPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-3-chloro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(37.4% yield). MS m/z=567.4 [M+H], calc 567.12 for C₃₀H₃₉ClN₆O₃.

Example 120

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(methylsulfonyl)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-(methylsulfonyl)benzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-(methylsulfonyl)benzamide(22.0% yield). MS m/z=611.4 [M+H], calc 610.77 for C₃₁H₄₂N₆O₅S.

Example 121

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethoxy)benzamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 3-(trifluoromethoxy)benzoic acid. The material was purified viapreparative HPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethoxy)benzamide(50.3% yield). MS m/z=617.4 [M+H], calc 616.67 for C₃₁H₃₉F₃N₆O₄. ¹H NMR(CDCl₃) δ ppm: 12.32 (br. s., 1H), 8.30-8.43 (m, 2H), 8.10 (d, J=0.8 Hz,1H), 7.28-7.31 (m, 1H), 7.01 (s, 1H), 5.34 (d, J=1.0 Hz, 1H), 4.77-4.91(m, 1H), 4.45-4.55 (m, 2H), 4.14-4.29 (m, 1H), 2.46-2.95 (m, 8H),2.20-2.27 (m, 2H), 1.73-1.89 (m, 4H), 1.58-1.73 (m, 5H), 1.41-1.57 (m,3H), 1.22 (d, J=6.6 Hz, 6H).

Example 122

(E)-N1-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)terephthalamide

The title compound was prepared using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide,using 4-carbamoylbenzoic acid. The material was purified via preparativeHPLC (0.1% NH₄OH in ACN/H₂O) to provide(E)-N1-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)terephthalamide(11.9% yield). MS m/z=576.2 [M+H], calc 575.71 for C₃₁H₄₁N₇O₄.

Example 123

(E)-4-Cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A: cis-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylicacid

The compound was made using a procedure analogous to that used in thepreparation ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing cis-4-aminocyclohexanecarboxylic acid.

Step B:tert-butyl-4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-piperazine-1-carboxylate

cis-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid(1.000 g, 3.34 mmol) was suspended in thionyl chloride (12.18 mL, 167mmol), and the mixture was stirred at RT for 30 minutes. The reactionmixture was concentrated in vacuo, dissolved in THF (33.4 mL), and thencooled to 0° C. under a nitrogen atmosphere. To the cooled reaction wasadded tert-butyl-piperazine-1-carboxylate (0.684 g, 3.67 mmol) as asolution in THF (1 mL). The reaction mixture was stirred at 0° C. for 15minutes and allowed to warm to RT and stirred overnight. To the reactionmixture was added additional tert-butyl-piperazine-1-carboxylate (0.684g, 3.67 mmol) in THF (1 mL) (×2, stirring for about 1 h after eachaddition). Upon completion, the reaction mixture was diluted withaqueous NH₄Cl and extracted with DCM (×2). The organic layers were driedover sodium sulfate, filtered and concentrated in vacuo. The residualmaterial was purified via silica gel chromatography, eluting withisocratic 90:10:1 DCM:MeOH:NH₄OH, to provide tert-butyl4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate(1.51 g, 70% yield) as a yellow solid. MS m/z=468.0 [M+H], calc 467.95for C₂₁H₃₀ClN₅O₅.

Step C: tert-butyl4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate

The title compound was made analogous to the preparation ofcis-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamideusing tert-butyl4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate.MS m/z=561.2 [M+H], calc 560.69 for C₂₈H₄₄N₆O₆.

Step D: tert-butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclo-hexanecarbonyl)piperazine-1-carboxylate

The title compound made analogous to the preparation ofcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide.MS m/z=531.3 [M+H], calc 530.70 for C₂₈H₄₆N₆O₄.

Step E: tert-butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)piperazine-1-carboxylate

tert-Butyl4-(cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate(0.200 g, 0.377 mmol) was suspended in THF (3.77 mL), and the mixturewas cooled to 0° C. under a nitrogen atmosphere. To this mixture wasadded a solution of 4-cyanobenzoyl isothiocyanate (0.078 g, 0.415 mmol)in 1.5 mL of THF. The reaction was stirred at RT for 30 minutes. PS-CDI(1.417 g, 1.884 mmol) was added (along with 6 mL of THF to account forswelling of the polymer-supported reagent) and the reaction was heatedat 60° C. for 1 hour. The solids were filtered off (rinsing well withTHF) and the filtrate was concentrated in vacuo. The residual materialwas purified via silica gel chromatography eluting with a gradient of 0%to 100% 90:10:1 DCM:MeOH:NH₄OH, to provide tert-butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexane-carbonyl)piperazine-1-carboxylateas an orange solid (0.227 g, 88% yield). MS m/z=685.2 [M+H], calc 684.83for C₃₇H₄₈N₈O₅.

Step F:(E)-4-Cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

tert-Butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarbonyl)piperazine-1-carboxylate(0.227 g, 0.331 mmol) was suspended in HCl (4M in dioxanes) (4.14 mL,16.57 mmol), and the resulting mixture was stirred at RT for 3 hour. Thereaction mixture was concentrated in vacuo, resuspended in DCM andwashed with aqueous NaHCO₃ solution. The aqueous layer was washed withDCM, and then the combined organics were dried over sodium sulfate,filtered and concentrated in vacuo. The material was purified viapreparative HPLC to yield the TFA salt, which was free-based using anSCX-ion exchange column to yield(E)-4-cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.076 g, 39.2% yield). MS m/z=585.2 [M+H], calc 584.71 for C₃₂H₄₀N₈O₃.¹H NMR (CDCl₃) δ ppm: 8.36-8.49 (m, 2H), 8.14 (d, J=0.7 Hz, 1H),7.71-7.78 (m, 2H), 7.10 (s, 1H), 4.74-4.88 (m, 1H), 4.46-4.59 (m, 2H),3.66-3.75 (m, 2H), 3.47-3.57 (m, 2H), 2.82-3.05 (m, 9H), 2.55-2.70 (m,3H), 2.08-2.19 (m, 2H), 1.58-1.91 (m, 10H), 1.42-1.54 (m, 3H).

Example 124

(E)-4-Fluoro-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared using a method analagous to thepreparation of(E)-4-cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide,using 4-fluorobenzoyl isothiocyanate. MS m/z=578.2 [M+H], calc 577.69for C₃₁H₄₀FN₇O₃. ¹H NMR (CDCl₃) δ ppm: 8.35 (dd, J=8.7, 5.7 Hz, 2H),8.09 (s, 1H), 7.01-7.20 (m, 3H), 4.75-4.96 (m, 1H), 4.50 (t, J=1.0 Hz,2H), 3.64-3.77 (m, 2H), 3.46-3.59 (m, 2H), 2.80-3.03 (m, 10H), 2.53-2.69(m, 4H), 2.08-2.19 (m, 2H), 1.72-1.90 (m, 5H), 1.60-1.71 (m, 4H),1.40-1.55 (m, 2H).

Example 125

(E)-3-Fluoro-N-(6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A:cis-4-(2-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

A suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(0.200 g, 0.587 mmol) and 2-(piperidin-4-yl)propan-2-ol (0.420 g, 2.93mmol) in 2-propanol (2.003 mL) was microwave irradiated for 1 hour at150° C. The reaction mixture was concentrated in vacuo, and the residualmaterial was purified via silica gel chromatography eluting withisocratic 90:10:1 DCM:MeOH:NH₄OH, to providecis-4-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideas a yellow solid (0.263 g, 100% yield). MS m/z=448.2 [M+H], calc 447.57for C₂₃H₃₇FN5O₄.

Step B:cis-4-(5-Amino-2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

The title compound was synthesized using a method analogous to thepreparation ofcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidestarting fromcis-4-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(yellow solid). MS m/z=418.2 [M+H], calc 417.59 for C₂₃H₃₉N₅O₂—

Step C:(E)-3-Fluoro-N-(6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-1-(cis-4-(isopropy-lcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to that usedto prepare tert-butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexane-carbonyl)piperazine-1-carboxylatestarting fromcis-4-(5-amino-2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(65.9% yield). MS m/z=565.2 [M+H], calc 564.69 for C₃₁H₄₁FN₆O₃. ¹H NMR(CDCl₃) δ ppm: 12.22 (br. s., 1H), 8.19 (d, J=0.5 Hz, 1H), 8.09 (dt,J=7.8, 1.2 Hz, 1H), 8.01 (ddd, J=10.0, 2.6, 1.5 Hz, 1H), 7.42 (td,J=7.9, 5.7 Hz, 1H), 7.15-7.22 (m, 1H), 5.30-5.35 (m, 1H), 4.93-5.07 (m,1H), 4.50-4.62 (m, 2H), 4.05-4.18 (m, 1H), 2.75-2.91 (m, 3H), 2.47-2.54(m, 1H), 2.13-2.21 (m, 2H), 1.71-1.98 (m, 6H), 1.36-1.64 (m, 6H), 1.23(s, 6H), 1.22 (d, J=6.55 Hz, 6H).

Example 126

(E)-4-Cyano-N-(6-(2-hydroxyethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A:cis-N-Isopropyl-4-(5-nitro-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

The title compound was synthesized using a method analogous to that usedto preparecis-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide,using 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (61.0% yield). MS m/z=451.2[M+H], calc 450.53 for C₂₂H₃₄N₄O₆.

Step B:cis-4-(5-Amino-2-(2-hydroxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexane-carboxamide

The title compound was synthesized using a method analogous to thepreparation ofcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidestarting fromcis-N-isopropyl-4-(5-nitro-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide,resulting in the deprotection of the -THP alcohol. MS m/z=337.2 [M+H],calc 336.43 for C₁₇H₂₈N₄O₃.

Step C:(E)-4-Cyano-N-(6-(2-hydroxyethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of tert-butyl4-(cis-4-((E)-2-(4-cyanobenzoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexane-carbonyl)piperazine-1-carboxylatestarting fromcis-4-(5-amino-2-(2-hydroxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexane-carboxamide(50.8% yield). MS m/z=491.1 [M+H], calc 490.55 for C₂₆H₃₀N₆O₄—

Example 127

(E)-4-Fluoro-N-(6-(2-hydroxyethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-4-cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(51.5% yield). MS m/z=484.2 [M+H], calc 483.54 for C₂₅H₃₀FN₅O₄.

Example 128

(E)-4-Fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-oxoethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

(E)-4-Fluoro-N-(6-(2-hydroxyethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.043 g, 0.089 mmol) was suspended in DCM (3.56 mL) under nitrogen, andthe reaction flask was cooled to 0° C. To the flask was addedDess-Martin periodinane (0.057 g, 0.133 mmol), and the reaction wasallowed to warm to RT and stirred for 1 hour. The reaction was quenchedwith aqueous NaHCO₃ (8 mL) and sodium thiosulfate (85 mg). The productwas extracted with 5% MeOH/DCM. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to afford(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-oxoethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas a light pink solid. MS m/z=482.0 [M+H], calc 481.52 for C₂₅H₂₈FN₅O₄.

Step B:(E)-4-Fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To a round bottom flask cooled at 0° C. charged with(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-oxoethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.056 g, 0.116 mmol) in DCE (0.775 mL) was added2-(piperidin-4-yl)propan-2-ol (0.083 g, 0.581 mmol) and NaBH(OAc)₃(0.074 g, 0.349 mmol). The reaction mixture was stirred at 0° C. for 1hour. The resulting mixture was quenched with saturated aqueous NaHCO₃,and extracted with DCM and EtOAc. The combined organic layers were driedover magnesium sulfate, filtered and concentrated in vacuo. The residualmaterial was purified via silica gel chromatography, eluting with agradient of 0% to 10% MeOH in EtOAc, followed by straight 90:10:1DCM:MeOH:NH₄OH to provide(E)-4-fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas an off-white solid (0.062 g, 88% yield). MS m/z=609.3 [M+H], calc608.75 for C₃₃H₄₅FN₆O₄.

Example 129

(E)-4-Cyano-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-4-fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(39.7% yield). MS m/z=616.2 [M+H], calc 615.77 for C₃₄H₄₅N₇O₄. ¹H NMR(CDCl₃) δ ppm: 12.32 (br. s, 1H), 8.38-8.47 (m, 2H), 8.14 (d, J=0.6 Hz,1H), 7.73-7.77 (m, 2H), 7.04 (s, 1H), 5.34 (d, J=1.0 Hz, 1H), 4.77-4.89(m, 1H), 4.74 (s, 1H), 4.50 (t, J=1.0 Hz, 2H), 4.22 (dd, J=7.7, 6.7 Hz,1H), 3.11-3.23 (m, 2H), 2.72-2.93 (m, 4H), 2.50-2.55 (m, 1H), 2.03-2.30(m, 4H), 1.72-1.89 (m, 6H), 1.28-1.56 (m, 3H), 1.23 (d, J=6.6 Hz, 6H),1.20 (s, 6H).

Example 130

(E)-3-Fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-4-fluoro-N-(6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(32.1% yield). MS m/z=609.2 [M+H], calc 608.75 for C₃₃H₄₅FN₆O₄—

Example 131

(E)-3-(N-Allylsulfamoyl)-N-(1-(trans-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A: trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylicacid

trans-4-Aminocyclohexanecarboxylic acid (5.01 g, 35.0 mmol) andpotassium carbonate (4.83 g, 35.0 mmol) were dissolved in water (20 mL).2,4-Dichloro-5-nitropyridine (6.75 g, 35.0 mmol) was added as a solutionin dioxane (40 mL), and the reaction was stirred at 80° C. for 8 hours.The dioxane solvent was removed under vacuum. The remaining aqueoussolution was acidified with aqueous 2N HCl (approx. pH 2-3), and theresulting precipitate was collected and washed with water, and then DCM.The solid was dried under high vacuum to yieldtrans-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride as a yellow solid (8.79 g, 74.8% yield). MS m/z=300.0[M+H], calc 299.71 for C₁₂H₁₄ClN₃O₄.

Step B:trans-4-(2-Chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride (0.500 g, 1.487 mmol) was suspended in THF (3 mL). Thionylchloride (0.434 mL, 5.95 mmol) was added to the suspension, and thereaction mixture was stirred at 20° C. for 2 hours. The resultingmixture was concentrated in vacuo. The solid was resuspended in THF (5mL) and then propan-2-amine (0.153 mL, 1.785 mmol) was added. Themixture was stirred at RT for 16 hours, and additional propan-2-amine(0.128 mL, 1.487 mmol) was added. Stirring at RT was continued for 1hour. The reaction mixture was diluted with DCM and washed withsaturated aqueous NaHCO₃ and brine. The organic layer was concentratedin vacuo, and the residual material was purified via silica gelchromatography, eluting with 20-100% EtOAc in hexanes, to yieldtrans-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideas a yellow solid (0.312 g, 61.6% yield). MS m/z=341.0 [M+H], calc340.81 for C₁₅H₂₁ClN₄O₃.

Step C:(E)-3-(N-Allylsulfamoyl)-N-(1-(trans-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of the remaining steps used to prepare(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo-[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide.MS m/z=652.2 [M+H], calc 651.82 for C₃₃H₄₅N₇O₅S. ¹H NMR (DMSO-d₆) δ ppm:12.72 (br. s., 1H), 8.57-8.63 (m, 1H), 8.45 (dt, J=7.75, 1.21 Hz, 1H),8.26 (s, 1H), 7.90-8.00 (m, 2H), 7.75 (t, J=7.8 Hz, 1H), 7.44 (d, J=1.0Hz, 1H), 7.04 (s, 1H), 5.61-5.77 (m, 1H), 5.10-5.20 (dq, J=17.1, 1.63Hz, 1H), 4.98-5.07 (dq, J=10.27, 1.47 Hz, 1H), 4.63-4.75 (m, 1H), 4.35(t, J=5.9 Hz, 2H), 3.77-3.92 (m, J=7.5 Hz, 1H), 3.46-3.52 (m, 2H), 2.65(t, J=5.9 Hz, 2H), 2.28-2.48 (m, J=4.4 Hz, 7H), 1.80-1.98 (m, 4H),1.55-1.72 (m, 2H), 1.43-1.54 (m, 4H), 1.32-1.42 (m, 2H), 1.07 (d, J=6.6Hz, 6H).

Example 132

cis-4-((E)-2-(Cyclohexylcarbamoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-4-(2-amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(0.150 g, 0.350 mmol) in THF (2.92 mL) was added cyclohexyl isocyanate(0.067 mL, 0.525 mmol). The resulting mixture was stirred at refluxovernight. The reaction mixture was concentrated in vacuo and purifiedvia silica gel chromatography, eluting with a gradient of 0% to 100%90:10:1 DCM:MeOH:NH₄OH. The product was further purified viareverse-phase preparative HPLC (0.1% TFA in ACN/H₂O, gradient 10% to 90%over 25 minutes) to provide the TFA salt of the desired product. Thematerial was free-based using an SCX ion-exchange column to yieldcis-4-((E)-2-(cyclohexylcarbamoylimino)-6-(2-(piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamideas a white solid (18.0% yield). MS m/z=554.2 [M+H], calc 553.74 forC₃₀H₄₇N₇O₃.

Example 133

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)morpholine-4-carboxamide

cis-4-(2-Amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide(0.200 g, 0.467 mmol), DIPEA (0.408 mL, 2.333 mmol) and phenylcarbonochloridate (0.235 mL, 1.867 mmol) were dissolved in THF (1.3 mL),and the reaction was stirred at 60° C. for 1 hour. Morpholine (0.407 mL,4.67 mmol) was added in DCM (1 mL), and heating was resumed at 50° C.for 2 hours. The solids were filtered and washed with DCM and thefiltrate was concentrated in vacuo. The residual material was purifiedvia reverse-phase preparative HPLC (0.1% TFA in ACN/H₂O, gradient 10% to90% over 25 min) to provide the TFA salt of the desired product. Thefree base was isolated using an SCX ion-exchange column to obtain(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)morpholine-4-carboxamideas a light purple solid (0.027 g, 10.68% yield). MS m/z=542.2 [M+H],calc 541.69 for C₂₈H₄₃N₇O₄—

Example 134

(E)-N-(1-(cis-4-(Isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)pyrrolidine-1-carboxamide

The title compound was synthesized using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)morpholine-4-carboxamide,using pyrrolidine as the amine source (4.5% yield). MS m/z=526.5 [M+H],calc 525.69 for C₂₈H₄₃N₇O₃. ¹H NMR (DMSO-d₆) δ ppm: 11.77 (s., 1H), 7.98(s, 1H), 7.62 (d, J=1.0 Hz, 1H), 6.79 (s, 1H), 4.45-4.58 (m, 1H), 4.30(t, J=1.0 Hz, 2H), 3.85-4.00 (m, 1H), 3.43-3.53 (m, 2H), 3.30-3.36 (m,2H), 2.61 (t, J=1.0 Hz, 2H), 2.52-2.59 (m, 2H), 2.36-2.47 (m, 5H),2.01-2.10 (m, 2H), 1.75-1.86 (m, 4H), 1.53-1.65 (m, 2H), 1.43-1.53 (m,6H), 1.32-1.42 (m, 2H), 1.08 (d, J=6.6 Hz, 6H).

Example 135

(E)-N-(1-(cis-4-Carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3-(N-allylsulfamoyl)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.MS m/z=509.2 [M+H], calc 508.59 for C₂₇H₃₃FN₆O₃. ¹H NMR (DMSO-d₆) δ ppm:12.63 (br. s., 1H), 8.28 (dd, J=8.7, 5.8 Hz, 2H), 8.22 (s, 1H), 7.37(br. s, 1H), 7.26-7.34 (m, 2H), 6.98 (s, 1H), 6.94 (br. s, 1H),4.66-4.80 (m, 1H), 4.34 (t, J=6.0 Hz, 2H), 2.60-2.69 (m, 3H), 2.52-2.58(m, 2H), 2.38-2.45 (m, 4H), 2.11-2.19 (m, 2H), 1.55-1.78 (m, J=17.2 Hz,4H), 1.44-1.55 (m, 4H), 1.32-1.43 (m, 2H).

Example 136

cis-4-(2-Amino-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide

Step A:cis-4-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(3.75 g, 11.18 mmol) in DCM (127 mL) at 0° C. was added thionyl chloride(4.08 mL, 55.9 mmol) dropwise. The reaction was stirred at 0° C. for 3hours and then at RT for 2 hours. The reaction was concentrated in vacuoand suspended in ACN and re-concentrated to remove residual thionylchloride. The residue was resuspended in ACN (102 mL, 11.18 mmol),cooled to 0° C., and to it was added 2-(piperidin-4-yl)propan-2-ol (5.60g, 39.1 mmol). The reaction was stirred at RT overnight. The mixture wasfiltered, and the filtrate concentrated in vacuo. The residual materialwas purified via silica gel chromatography, eluting with 90:10:1DCM:MeOH:NH₄OH to providecis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(4.64 g, 10.07 mmol, 90% yield) as an orange solid. MS m/z=461.4 [M+H],calc 460.61 for C₂₅H₄₀N₄O₄.

Step B:cis-4-(2-Amino-5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)phenylamino)-N-isopropylcyclohexanecarboxamide

To a flask under nitrogen atmosphere, Pd/C (10%) (0.460 g, 0.432 mmol)(water wet) was diluted with MeOH (28.8 mL). To the slurry was addedcis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(1.99 g, 4.32 mmol), followed by ammonium formate (2.72 g, 43.2 mmol).The flask was closed and stirred at RT for 30 minutes. The reaction wasfiltered through a pad of Celite® brand filter aid, washing with MeOH.The filtrate was concentrated in vacuo, and was dissolved in 90:10:1DCM:MeOH:NH₄OH and washed with water (×2). The organic layer was driedwith sodium sulfate, filtered and concentrated in vacuo to yieldcis-4-(2-amino-5-44-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)phenylamino)-N-isopropylcyclohexanecarboxamideas a red solid. MS m/z=431.2, calc 430.63 C₂₅H₄₂N₄O₂—

Step C:cis-4-(2-Acetamido-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide

The title compound was synthesized using a method analogous to thepreparation ofcis-4-(2-acetamido-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide.MS m/z=498.2 [M+H], calc 497.67 for C₂₈H₄₃N₅O₃.

Step D:cis-4-(2-Amino-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide

The title compound was synthesized using a method analogous to thepreparation ofcis-4-(2-amino-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-1-yl)-N-isopropylcyclohexanecarboxamide.MS m/z=456.2 [M+H], calc 455.64 for C₂₆H₄₁N₅O₂.

Example 137

(E)-3,5-Difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo-[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide(19.9% yield). MS m/z=596.2 [M+H], calc 575.72 for C₃₃H₄₃F₂N₅O₃. ¹H NMR(DMSO-d₆) δ ppm: 12.81 (s, 1H), 7.85 (dd, J=8.4, 2.3 Hz, 2H), 7.56-7.64(m, J=7.6 Hz, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.38 (tt, J=9.0, 2.4 Hz, 1H),7.18 (dd, J=8.2, 1.0 Hz, 1H), 4.78-4.90 (m, 1H), 4.00-4.11 (m, 1H), 3.99(s, 1H), 3.50 (s, 2H), 2.85-2.92 (m, 2H), 2.63-2.82 (m, 2H), 2.51-2.56(m, 1H), 2.06-2.19 (m, 2H), 1.69-1.91 (m, 4H), 1.56-1.69 (m, 4H),1.18-1.35 (m, 2H), 1.12-1.18 (m, 1H), 1.09 (d, J=3.6 Hz, 6H), 1.02 (s,6H).

Example 138

(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)isonicotinamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using isonicotinic acid (21.3% yield). MS m/z=561.4 [M+H], calc 560.73for C₃₂H₄₄N₆O₃.

Example 139

(E)-4-Cyano-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 4-cyanobenzoic acid (20.5% yield). MS m/z=585.4 [M+H], calc 584.75for C₃₄H₄₄N₆O₃. ¹H NMR (DMSO-d₆) δ ppm: 12.83 (br. s., 1H), 8.41 (d,J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.58 (s,1H), 7.50 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.81-4.92 (m, 1H),4.01-4.09 (m, 1H), 4.00 (s, 1H), 3.50 (s, 2H), 2.83-2.93 (m, 2H),2.66-2.80 (m, 2H), 2.52-2.56 (m, 2H), 2.10-2.19 (m, 2H), 1.79-1.89 (m,2H), 1.68-1.79 (m, 2H), 1.58-1.67 (m, 4H), 1.18-1.31 (m, 2H), 1.11 (d,J=6.5 Hz, 6H), 1.02 (s, 6H).

Example 140

(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using nicotinic acid (23.2% yield). MS m/z=561.3 [M+H], calc 560.73 forC₃₂H₄₄N₆O₃.

Example 141

(E)-3,4-Difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3,4-difluorobenzoic acid (16.4% yield). MS m/z=596.3 [M+H], calc595.72 for C₃₃H₄₃F₂N₅O₃—

Example 142

(E)-3-Cyano-5-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-cyano-5-fluorobenzoic acid (17.6% yield). MS m/z=603.4 [M+H],calc 602.74 for C₃₄H₄₃FN₆O₃. ¹H NMR (DMSO-d₆) δ ppm: 12.87 (br. s., 1H),8.43 (s, 1H), 8.32 (d, J=1.0 Hz, 1H), 7.96-8.03 (m, 1H), 7.58-7.65 (m,2H), 7.52 (d, J=8.1 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 4.78-4.90 (m, 1H),4.02-4.13 (m, 1H), 4.00 (s, 1H), 3.50 (s, 2H), 2.85-2.92 (m, 2H),2.72-2.84 (m, 2H), 2.52-2.57 (m, 1H), 2.06-2.15 (m, 2H), 1.68-1.90 (m,4H), 1.58-1.67 (m, 4H), 1.19-1.31 (m, 2H), 1.11-1.18 (m, 1H), 1.08 (d,J=1.0 Hz, 6H), 1.02 (s, 6H).

Example 143

(E)-3-Cyano-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-cyanobenzoic acid (20.2% yield). MS m/z=585.4 [M+H], calc 584.76for C₃₄H₄₄N₆O₃—

Example 144

(E)-3-Chloro-5-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-chloro-5-fluorobenzoic acid (21.4% yield). MS m/z=612.3 [M+H],calc 612.19 for C₃₃H₄₃ClFN₅O₃. ¹H NMR (DMSO-d₆) δ ppm: 12.82 (br. s.,1H), 7.96-8.05 (m, 2H), 7.54-7.66 (m, 3H), 7.51 (d, J=8.1 Hz, 1H), 7.18(d, J=8.1 Hz, 1H), 4.80-4.91 (m, 1H), 4.01-4.10 (m, 1H), 4.00 (s, 1H),3.50 (s, 2H), 2.84-2.92 (m, 2H), 2.64-2.79 (m, 2H), 2.51-2.56 (m, 2H),2.05-2.19 (m, 2H), 1.79-1.89 (m, 2H), 1.67-1.79 (m, 2H), 1.59-1.67 (m,4H), 1.18-1.31 (m, 2H), 1.10 (d, J=6.5 Hz, 6H), 1.02 (s, 6H).

Example 145

(E)-3-Chloro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-chlorobenzoic acid (21.4% yield). MS m/z=594.4 [M+H], calc594.20 for C₃₃H₄₄ClN₅O₃.

Example 146

(E)-3-Chloro-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-chloro-4-fluorobenzoic acid (21.4% yield). MS m/z=612.3 [M+H],calc 612.19 for C₃₃H₄₃ClFN₅O₃.

Example 147

(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-(trifluoromethyl)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 3-(trifluoromethyl)benzoic acid (16.1% yield). MS m/z=628.4 [M+H],calc 627.75 for C₃₄H₄₄F₃N₅O₃.

Example 148

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-(trifluoromethyl)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 4-fluoro-3-(trifluoromethyl)benzoic acid (14.5% yield). MSm/z=646.4 [M+H], calc 645.74 for C₃₄H₄₃F₄N₅O₃.

Example 149

(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using benzoic acid (22.3% yield). MS m/z=560.4 [M+H], calc 559.75 forC₃₃H₄₅N₅O₃.

Example 150

(E)-4-Cyano-3-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 4-cyano-3-fluorobenzoic acid (21.5% yield). MS m/z=603.4 [M+H],calc 602.75 for C₃₄H₄₃FN₆O₃.

Example 151

(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-methoxybenzamide

The title compound was synthesized using a method analogous to thepreparation of(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,using 4-methoxybenzoic acid (7.8% yield). MS m/z=590.2 [M+H], calc589.77 for C₃₄H₄₇N₅O₄—

Example 152

(E)-3-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was synthesized synthesized using a method analogousto the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(39.5% yield). MS m/z=578.2 [M+H], calc 577.73 for C₃₃H₄₄FN₅O₃. ¹H NMR(DMSO-d₆) δ ppm: 12.80 (br. s., 1H), 8.10 (d, J=1.0 Hz, 1H), 7.93 (d,J=1.0 Hz, 1H), 7.43-7.69 (m, J=5.8 Hz, 4H), 7.29-7.39 (m, 1H), 7.11-7.23(m, 1H), 4.80-4.92 (m, 1H), 4.56 (s, 1H), 3.94-4.13 (m, 2H), 3.44-3.58(m, 2H), 2.81-2.96 (m, 2H), 2.64-2.80 (m, 2H), 2.51-2.56 (m, 2H),2.09-2.21 (m, 2H), 1.54-1.92 (m, 7H), 1.20-1.37 (m, 2H), 1.10 (d, J=6.6Hz, 6H), 1.02 (s, 6H).

Example 153

4-Fluoro-N-(6-((4-methoxybenzyl)oxy)-1-(cis-4-((1-methylethyl)carbamoyl)cyclohexyl)-1H-benzimidazol-2-yl)benzamideStep A: 2-Fluoro-4-(4-methoxybenzyloxy)-1-nitrobenzene

To a solution of 3-fluoro-4-nitrophenol (2.96 g, 18.81 mmol) in DMF(18.81 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.55 mL, 18.81mmol) and potassium carbonate (5.20 g, 37.6 mmol). The reaction mixturewas stirred at 50° C. for 16 hours. The mixture was diluted with EtOAc(100 mL), washed with water, and the aqueous layer was back-extractedwith EtOAc (25 mL). The combined organic layers were washed with 1 Maqueous NaOH (20 mL) and then with brine. The organic layer was driedover Na₂SO₄, filtered and evaporated. The yellow solid was trituratedwith ether (20 mL), and the solid was collected, rinsing with ether (5mL). The title compound was obtained as a yellow solid (4.39 g, 84%yield).

Step B:cis-N-Isopropyl-4-(5-(4-methoxybenzyloxy)-2-nitrophenylamino)cyclohexanecarboxamide

A mixture of 2-fluoro-4-(4-methoxybenzyloxy)-1-nitrobenzene (507 mg,1.82 mmol), cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride(404 mg, 1.82 mmol), DIPEA (0.70 mL, 4.02 mmol) and ACN (3.6 mL) wereplaced in a sealed tube, and the tube was heated at 80° C. for 6 hours.The mixture was allowed to cool and evaporated. The residue was dilutedwith DCM (15 mL), washed with water (×2), and then washed with brine.The organic layer was dried over Na₂SO₄. The mixture was purified viaflash chromatography using a linear gradient of 0% to 10% MeOH in DCM.The title compound was collected as a yellow solid (476 mg, 59% yield).

Step C:4-Fluoro-N-(4-fluorobenzoyl)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide

To a solution ofcis-N-isopropyl-4-(5-(4-methoxybenzyloxy)-2-nitrophenylamino)cyclohexanecarboxamide(452 mg, 1.024 mmol) in MeOH (5 mL) was added AcOH (0.293 mL, 5.12 mmol)and zinc (669 mg, 10.24 mmol), and the resulting mixture was stirred atRT for 3 hours. The mixture was filtered through a pad of Celite® brandfilter aid and evaporated to affordcis-4-(2-amino-5-(4-methoxybenzyloxy)phenylamino)-N-isopropylcyclohexanecarboxamide(400 mg).

To a solution ofcis-4-(2-amino-5-(4-methoxybenzyloxy)phenylamino)-N-isopropylcyclohexanecarboxamide(400 mg, 0.972 mmol) in EtOH (4.8 mL) was added cyanic bromide (165 mg,1.555 mmol) and the mixture was stirred at RT for 2 hours. The solventwas evaporated, and the residue was diluted with DCM (about 10 mL),washed with water, 1N aqueous NaOH, and brine. The organic layer wasdried over Na₂SO₄, filtered and the solvent was removed to affordcis-4-(2-amino-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide(424 mg).

To a solution ofcis-4-(2-amino-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide(424 mg, 0.971 mmol) and 4-fluorobenzoyl chloride (0.172 mL, 1.457 mmol)in DCM was added TEA (0.271 mL, 1.943 mmol), and the resulting mixturewas stirred at RT for 10 minutes. The mixture was evaporated, and theresidue diluted with DCM, washed with water, brine, and the organiclayer dried over Na₂SO₄. The mixture was purified via flashchromatography using a linear gradient of 0% to 10% MeOH in DCM. Thetitle compound was obtained as a tan foam (442 mg, max 80% yield,mixture of the mono and bis-acylated products).

Step D:4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide

To a solution of4-fluoro-N-(4-fluorobenzoyl)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide(442 mg, 0.649 mmol, as a mixture with the mono-acylated material) inMeOH (3.2 mL) and dioxane (3.2 mL) was added a flake of sodium hydroxide(46.7 mg, 1.169 mmol), and the mixture was stirred at RT for 1 hour. Themixture was evaporated and the residue diluted with DCM, washed with 1 Naqueous NaOH, brine, and the organic layer dried over Na₂SO₄. Theresidue was purified via flash chromatography using a linear gradient of0% to 50% EtOAc in hexanes. The title compound was collected as a whitesolid (275 mg, 76% yield). M/Z calc'd for C₃₂H₃₅FN₄O₄: 558.65. found 559[M+H].

Example 154

4-Fluoro-N-(6-hydroxy-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide

To a solution of4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide(232 mg, 0.415 mmol) in DCM was added TFA (0.96 mL, 1.246 mmol), and themixture was stirred at RT for 90 minutes. Additional TFA (0.96 mL, 1.246mmol) was added, and the mixture was stirred at RT for 1 hour longer.The mixture was diluted with DCM, washed with 1 N aqueous NaOH, and thewater layer back-extracted with DCM. The aqueous layer was adjusted topH 8, and the pale green solid was collected and rinsed with 2 mL water.The solid was dissolved in ether and washed with brine, dried overNa₂SO₄, filtered, and evaporated. The title compound was obtained as awhite sold (153 mg, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d,J=8 Hz, 6H) 1.59 (m, 2H) 1.65-1.82 (m, 2H) 2.02-2.19 (m, 2H) 2.46-2.58(m, 1H) 2.62-2.79 (m, 2H) 3.93-4.07 (m, 1H) 4.70-4.85 (m, 1H) 6.67 (dd,J=8.61, 2.15 Hz, 1H) 7.03 (d, J=2.05 Hz, 1H) 7.14-7.28 (m, 2H) 7.33 (d,J=8.51 Hz, 1H) 7.64 (d, J=7.82 Hz, 1H) 8.16-8.38 (m, 2H) 9.40 (s, 1H)12.58 (s, 1H). M/Z calc'd for C₂₄H₂₇FN₄O₃: 438.50. found 439 [M+H].

Example 155

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: 1-(2-(3-Fluoro-4-nitrophenoxy)ethyl)piperidine

A mixture of 3-fluoro-4-nitrophenol (3.07 g, 19.54 mmol),1-(2-chloroethyl)piperidine hydrochloride (3.60 g, 19.54 mmol), cesiumcarbonate (19.10 g, 58.6 mmol) and potassium iodide (1.622 g, 9.77 mmol)were combined with DMF (19.54 mL), and the mixture was heated at 50° C.for 36 hours. The resulting mixture was diluted with EtOAc (50 mL),washed with water (100 mL) and the water layer extracted with EtOAc (30mL). The combined organic layers were washed with water (20 mL×2), 1Naqueous NaOH, and brine, and the organic layer was dried over Na₂SO₄,filtered and evaporated. The residue was purified via flashchromatography using a linear gradient of 0% to 5% of 1% NH₄OH in MeOHin DCM. The title compound was isolated as a yellow liquid (662 mg, 13%yield).

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution of 1-(2-(3-fluoro-4-nitrophenoxy)ethyl)piperidine (220 mg,0.820 mmol) and cis-4-amino-N-isopropylcyclohexanecarboxamidehydrochloride (190 mg, 0.861 mmol) in ACN (0.8 mL) was added DIPEA(0.301 mL, 1.722 mmol). The mixture was heated at 80° C. in a sealedtube for 14 hours, and then additionalcis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (38 mg,0.172 mmol) and DIPEA (0.100 mL, 0.574 mmol) were added. The resultingmixture was heated an additional 24 hours. The mixture was diluted withDCM (5 mL), washed with water/brine mixture, brine, and the organiclayer was dried over Na₂SO₄, filtered and evaporated to affordcis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide.

To a solution ofcis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide(350 mg, 0.809 mmol) in MeOH (4.0 mL) was added AcOH (0.463 mL, 8.09mmol) and zinc (423 mg, 6.47 mmol), and the mixture was stirred at RTfor 1 hour. The mixture was filtered through a pad of Celite® brandfilter aid and evaporated to affordcis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide.

The title compound was prepared fromcis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.The product was isolated as an off-white solid (96 mg, 15% yield). M/Zcalc'd for C₃₁H₄₀FN₅O₃: 549.68. found 550 [M+H].

Example 156

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To a solution ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(100 mg, 0.293 mmol) and conc. HCl (0.072 mL, 0.880 mmol) in EtOH (3.0mL) under nitrogen was added Pd/C (10% wt) (156 mg, 0.147 mmol) andammonium formate (185 mg, 2.93 mmol), and the mixture was stirred at RTfor 30 minutes. The mixture was filtered through a pad of Celite® brandfilter aid and evaporated. The residue was diluted with 10% IPA in DCM,and washed with 1 N NaOH and then with saturated aqueous NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and the solvent wasremoved to afford4-(3-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as anoff-white solid.

The title compound was prepared from4-(3-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using aprocedure analogous to the preparation of cis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylateisolated as an off-white solid (8 mg, 1% yield). M/Z calc'd forC₂₃H₂₆FN₅O₂: 423.48. found 424 [M+H].

Example 157

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-methoxy-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-methoxy-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

To an ice-bath cooled suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(400 mg, 1.174 mmol) in THF (2.3 mL) was added sodium methoxide (25 wt.% in MeOH (0.859 mL, 3.76 mmol)). The mixture was stirred in an ice bathfor 1 minute. The ice bath was removed and the reaction was stirred for30 minutes. The mixture was diluted with 10% IPA/DCM (5 mL) and washedwith saturated aqueous NaHCO₃ (1 mL). The layers were separated, and theorganic layer was dried with Na₂SO₄ and the mixture purified via flashchromatography using a linear gradient of 0% to 5% of 1% NH₄OH in MeOHin DCM. The title compound was collected as a yellow solid (289 mg,73%).

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-methoxy-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To solution ofcis-N-isopropyl-4-(2-methoxy-5-nitropyridin-4-ylamino)cyclohexanecarboxamide(264 mg, 0.785 mmol) in AcOH (1.5 μmL) was added iron powder (219 mg,3.92 mmol), and the mixture was heated to 100° C. for 5 minutes. Themixture was allowed to cool to RT, was diluted with 10% MeOH/DCM, andwas filtered through a pad of Celite® brand filter aid and concentrated.The mixture was purified via flash chromatography using a lineargradient of 0% to 10% of 1% NH₄OH in MeOH in DCM.Cis-4-(5-amino-2-methoxypyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas isolated as a red film (211 mg).

To a 0° C. cooled solution ofcis-4-(5-amino-2-methoxypyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(211 mg, 0.689 mmol) in 1 mL THF, was added a suspension of4-fluorobenzoyl isothiocyanate (250 mg, 1.377 mmol) in THF (3.4 mL). Theresulting reaction mixture was stirred at 0° C. for 15 minutes. The icebath was removed, and the mixture was stirred for 15 minutes at RT. Tothe mixture were added EDC (396 mg, 2.066 mmol) and DIPEA (0.433 mL,2.479 mmol), and the flask was heated at 60° C. for 1 hour. Theresulting mixture was allowed to cool to RT, and the solvents wereremoved. The residue was dissolved in 10% IPA in DCM and was washed withwater and brine. The organic layer was dried over Na₂SO₄ and filtered.The mixture was purified via flash chromatography using a lineargradient of 0% to 5% of 1% NH₄OH in MeOH in DCM. The title compound wascollected as an off-white solid. The solid was partitioned with 10%IPA/EtOAc and was washed with 1 mL:2 mL saturated aqueous NH₄Cl/water,and brine. The organic layer was dried over Na₂SO₄, filtered and thesolvents were removed to afford the title compound as an off-white solid(212 mg, 68%). M/Z calc'd for C₂₄H₂₈FN₅O₃: 453.51. found 454 [M+H].

Example 158

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(pyridin-2-yloxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

A microwave vial was charged with4-fluoro-N-(6-hydroxy-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide(56 mg, 0.128 mmol), 2-chloropyridine (0.036 mL, 0.383 mmol), cesiumcarbonate (166 mg, 0.511 mmol), and NMP (0.6 mL) then irradiated in themicrowave at 160° C. for 6 hours. The mixture was diluted with EtOAc,washed with water, the water layer back extracted with EtOAc, and thecombined organics were washed with brine. The organic layer was driedover Na₂SO₄ and filtered. The mixture was purified via flashchromatography using a linear gradient of 0% to 10% MeOH in DCM. Thematerial was further purified by reverse-phase preparative HPLC using a0.1% TFA in ACN/H₂O, gradient 10% to 90%. The material was partitionedbetween saturated aqueous NaHCO₃ and 5% IPA/DCM, the organic layerwashed with brine, dried over Na₂SO₄, filtered and evaporated. The titlecompound was isolated as an off-white solid (32 mg, 35% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.98 (d, J=8.00 Hz, 6H) 1.54-1.82 (m, 4H)2.01-2.14 (m, 2H) 2.42-2.56 (m, 1H) 2.56-2.77 (m, 2H) 3.75-3.93 (m, 1H)4.80-4.95 (m, 1H) 6.97 (dd, J=8.56, 2.10 Hz, 1H) 6.95-7.10 (m, 1H)7.00-7.18 (m, 1H) 7.20-7.29 (m, 2H) 7.48 (d, J=2.05 Hz, 1H) 7.51-7.62(m, 2H) 7.80-7.90 (m, 1H) 8.07-8.19 (m, 1H) 8.27-8.38 (m, 2H) 12.81 (s,1H). M/Z calc'd for C₂₉H₃₀FN₅O₃: 515.58. found 516 [M+H].

Example 159

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

To an ice-bath cooled solution of 2-methoxyethanol (0.296 mL, 3.76 mmol)in THF (2.3 mL) was added sodium hydride (150 mg, 3.76 mmol), and themixture was stirred for 20 minutes. To the mixture was addedcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(400 mg, 1.174 mmol), and the flask was removed from the ice bath andthe reaction was stirred for 2 hours. The reaction was quenched withwater and diluted with DCM, washed with water, saturated aqueous NaHCO₃,and the organic layer dried over Na₂SO₄ and filtered through Celite®brand filter aid. The material was purified via flash chromatographyusing a linear gradient of 0% to 5% of 1% NH₄OH in MeOH in CH₂Cl₂. Thetitle compound was collected as a yellow solid (273 mg, 61% yield).

Step B:cis-4-(5-Amino-2-(2-methoxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

The title compound was prepared fromcis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a procedure analogous to that used in the preparation ofcis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide.

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To an ice-bath cooled solution ofcis-4-(5-amino-2-(2-methoxyethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(156 mg, 0.445 mmol) in THF (0.8 mL) was added 4-fluorobenzoylisothiocyanate (161 mg, 0.890 mmol) as a solution in THF (2 mL). Themixture was stirred 15 minutes, and then stirred another 30 minutes atRT. DIPEA (0.194 mL, 1.113 mmol) and EDC (213 mg, 1.113 mmol) wereadded, and the mixture was heated to 60° C. for 1 hour. The mixture wasevaporated, and the residue was dissolved with 5% IPA/EtOAc (5 mL),washed with 1:1 aqueous NH₄Cl (sat)/water, [1 mL total volume (×2)],brine, and the organic layer was dried over Na₂SO₄ and filtered. Themixture was purified via flash chromatography using a linear gradient of0% to 5% of 1% NH₄OH in MeOH in DCM. The title compound was collected asa white solid (110 mg, 50% yield). M/Z calc'd for C₂₆H₃₂FN₅O₄: 497.56.found 498 [M+H].

Example 160

(E)-N-(6-Chloro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamideStep A:cis-4-(5-Amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(400 mg, 1.174 mmol) in MeOH (2.3 mL) was added SnCl₂ (890 mg, 4.69mmol), and the mixture was stirred at reflux for 2 hours. The mixturewas evaporated and partitioned between 10% IPA/DCM and saturated NaHCO₃.The solids were removed by filtration through Celite® brand filter aid,and the organic layer was washed with water, saturated NaHCO₃, driedover Na₂SO₄ and filtered. The mixture was purified via flashchromatography using a linear gradient of 0% to 10% of 1% NH₄OH in MeOHin DCM. The title compound was collected as a white solid (160 mg, 44%yield).

Step B:(E)-N-(6-Chloro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used in the preparation ofcis-methyl4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate.Isolated as an off-white solid (34 mg, 15% yield). M/Z calc'd forC₂₃H₂₅ClFN₅O₂: 457.93. found 458 [M+H].

Example 161

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: 4-(2-(3-Fluoro-4-nitrophenoxy)ethyl)morpholine

The title compound was prepared with 4-(2-chloroethyl)morpholinehydrochloride using a procedure analogous to that used for1-(2-(3-fluoro-4-nitrophenoxy)ethyl)piperidine (4.37 g, 79% yield).

Step B:cis-N-Isopropyl-4-(5-(2-morpholinoethoxy)-2-nitrophenylamino)cyclohexanecarboxamide

The title compound was prepared from4-(2-(3-fluoro-4-nitrophenoxy)ethyl)morpholine using a procedureanalogous to that used to preparecis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide(425 mg, 98% yield).

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution ofcis-N-isopropyl-4-(5-(2-morpholinoethoxy)-2-nitrophenylamino)-cyclohexanecarboxamide(425 mg, 0.978 mmol) in AcOH (1.0 mL) was added iron (273 mg, 4.89mmol), and the mixture was heated to 100° C. for 40 minutes. The mixturewas diluted with MeOH and filtered through a pad of Celite® brand filteraid and evaporated. The residue was dissolved in THF (5 mL) and zinc(512 mg, 7.82 mmol) and AcOH (0.560 mμL, 9.78 mmol) were added. Themixture was stirred at RT for 1 hour and was filtered through a pad ofCelite® brand filter aid upon complete conversion. The mixture waspurified via flash chromatography using a linear gradient of 0% to 10%of 1% NH₄OH in MeOH in DCM. The desired compoundcis-4-(2-amino-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamidewas obtained as a red film.

The title compound was prepared fromcis-4-(2-amino-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used for(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.Isolated as an off-white solid (19 mg, 35% yield). M/Z calc'd forC₃₀H₃₈FN₅O₄: 551.65. found 552 [M+H].

Example 162

(E)-4-Fluoro-N-(6-hydroxy-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To a RT suspension of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-methoxy-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(30 mg, 0.066 mmol) and sodium iodide (69.4 mg, 0.463 mmol) in ACN (0.6mL) was added TMS-C₁ (0.059 mL, 0.463 mmol) and water (10 μL), and themixture was heated at 60° C. After 2 hours and 4 hours, additionalTMS-Cl portions (0.059 mL, 0.463 mmol) were added, and the mixture wasstirred at 60° C. for a total reaction time of 20 hours. The materialwas purified by reverse-phase preparative HPLC using 0.1% TFA inACN/H₂O, gradient 10% to 90% over 15 minutes. The combined fractionswere freebased with saturated aqueous NaHCO₃ and extracted with 10%IPA/DCM, dried over Na₂SO₄, filtered and evaporated. The title compoundwas obtained as a white solid (8 mg, 21% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.08 (d, J=8 Hz, 6H) 1.50-1.60 (m, 2H) 1.62-1.82 (m, 2H)2.05-2.08 (m, 2H) 2.49-2.51 (m, 1H) 2.55-2.74 (m, 2H) 3.97-4.02 (m, 1H)4.60-4.70 (m, 1H) 6.38 (s, 1H) 7.20-7.30 (m, 2H) 7.48-7.52 (m, 1H) 7.64(d, J=7.63 Hz, 1H) 8.29 (dd, J=8.22, 5.97 Hz, 2H) 11.10 (br. s., 1H)12.26 (br. s., 1H). M/Z calc'd for C₂₃H₂₆FN₅O₃: 439.48. found 440 [M+H].

Example 163

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-morpholinoethylamino)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

A glass microwave reaction vessel was charged withcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(200 mg, 0.587 mmol) and 2-morpholinoethanamine (0.092 mL, 0.704 mmol)in 2-propanol. A drop of HCl (2N in ether) was added, and the reactionmixture was stirred and irradiated in a microwave at 175° C. for 2hours. Additional 2-morpholinoethanamine (0.030 mL, 0.24 mmol) wasadded, and the mixture was heated an additional 20 minutes. The mixturewas evaporated and the residue diluted with 10% IPA/DCM, washed withwater, brine, and the organic layer dried over Na₂SO₄. The mixture waspurified via flash chromatography using a linear gradient of 0% to 10%of 1% NH₄OH in MeOH in DCM. Intermediatecis-N-isopropyl-4-(2-(2-morpholinoethylamino)-5-nitropyridin-4-ylamino)cyclohexanecarboxamidewas isolated as a yellow film (128 mg).

Diaminecis-4-(5-amino-2-(2-morpholinoethylamino)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas prepared fromcis-N-isopropyl-4-(2-(2-morpholinoethylamino)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a procedure analogous to that used in the preparation ofcis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(73 mg).

The title compound was prepared fromcis-4-(5-amino-2-(2-morpholinoethylamino)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used to prepare(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.Isolated as an off-white solid (23 mg, 23% yield). M/Z calc'd forC₂₉H₃₈FN₇O₃: 551.66. found 552 [M+H].

Example 164

(E)-N-(6-(2-(1H-1,2,4-Triazol-1-yl)ethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

Intermediatecis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas prepared in 2 steps from 2-(1H-1,2,4-triazol-1-yl)ethanol using aprocedure analogous to that used to preparecis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide(104 mg).

Diaminecis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas prepared fromcis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used forcis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(104 mg).

The title compound was prepared fromcis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used to prepare(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.Isolated as an off-white solid (62 mg, 43% yield, last step). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.55 Hz, 6H) 1.57-1.62 (m, 2H)1.69-1.73 (m, 2H) 2.02-2.16 (m, 2H) 2.50-2.51 (m, 1H) 2.57-2.79 (m, 2H)3.92-4.02 (m, 1H) 4.60-4.65 (m, 4H) 4.70-4.80 (m, 1H) 6.99 (s, 1H) 7.25(dd, J=8.85, 8.85 Hz, 2H) 7.65 (d, J=7.82 Hz, 1H) 7.98 (s, 1H) 8.22 (s,1H) 8.28-8.36 (m, 2H) 8.53 (s, 1H) 12.70 (s, 1H). M/Z calc'd forC₂₇H₃₁FN₈O₃: 534.59. found 535 [M+H].

Example 165

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(3-morpholinopropoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Intermediatecis-N-isopropyl-4-(2-(3-morpholinopropoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamidewas prepared with 3-morpholinopropan-1-ol using a 2 step procedureanalogous to that used to preparecis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide(200 mg).

Diaminecis-4-(5-amino-2-(3-morpholinopropoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas prepared fromcis-N-isopropyl-4-(2-(3-morpholinopropoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a procedure analogous to that used forcis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(130 mg).

The title compound was prepared fromcis-4-(5-amino-2-(3-morpholinopropoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used to prepare(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamidewith 1.3 equivalents of 4-fluorobenzoyl isothiocyanate. Isolated as anoff-white solid (98 mg, 104% yield). M/Z calc'd for C₃₀H₃₉FN₆O₄: 566.67.found 567 [M+H].

Example 166

(E)-4-Fluoro-N-(5-fluoro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

Intermediate 4-(2-(2,5-difluoro-4-nitrophenoxy)ethyl)morpholine wasprepared from 4-(2-chloroethyl)morpholine hydrochloride using aprocedure analogous to that used to prepare1-(2-(3-fluoro-4-nitrophenoxy)ethyl)piperidine (900 mg).

Intermediatecis-4-(4-Fluoro-5-(2-morpholinoethoxy)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamidewas prepared from 4-(2-(2,5-difluoro-4-nitrophenoxy)ethyl)morpholineusing a procedure analogous to that used to preparecis-N-isopropyl-4-(5-(4-methoxybenzyloxy)-2-nitrophenylamino)cyclohexanecarboxamide(272 mg).

Diaminecis-4-(2-amino-4-fluoro-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamidewas prepared fromcis-4-(4-fluoro-5-(2-morpholinoethoxy)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used to prepare4-(3-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (161 mg,81% yield).

The title compound was prepared fromcis-4-(2-amino-4-fluoro-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used to prepare(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.The product was isolated as an off-white solid (161 mg, 81% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=8 Hz, 6H) 1.53-1.66 (m, 2H)1.70-1.80 (m, 2H) 2.00-2.08 (m, 2H) 2.52-2.60 (m, 1H) 2.70-2.91 (m, 8H)3.49-3.70 (m, 4H) 3.89-4.08 (m, 1H) 4.27 (t, J=6.06 Hz, 2H) 4.93 (br.s., 1H) 7.24 (dd, J=8.85, 8.85 Hz, 2H) 7.38 (d, J=10.76 Hz, 1H) 7.77 (d,J=7.73 Hz, 2H) 8.29 (dd, J=8.61, 5.97 Hz, 2H) 12.73 (s, 1H). M/Z calc'dfor C₃₀H₃₇F₂N₅O₄: 569.64. found 570 [M+H].

Example 167

tert-Butyl2-(4-((E)-2-(4-fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)acetateStep A: tert-Butyl 2-(4-hydroxypiperidin-1-yl)acetate

To a heated (40° C.) solution of tert-butyl 2-bromoacetate (7.38 mL,49.9 mmol) in THF (10 mL) was added dropwise a solution ofpiperidin-4-ol (5.050 g, 49.9 mmol) and TEA (6.96 mL, 49.9 mmol) in THF(50 mL). The mixture was refluxed for 2 hours and then cooled to RT andfiltered through a pad of Celite® brand filter aid. The filtrate wasevaporated and the residue diluted with EtOAc (50 mL), washed with water(50 mL), brine (10 mL), and the organic layer dried over Na₂SO₄,filtered and evaporated. The material was purified via flashchromatography using a linear gradient of 0% to 10% of 1% NH₄OH in MeOHin DCM. The title compound was isolated as an off-white solid (4.865 g,45% yield).

Step B: tert-Butyl2-(4-((E)-2-(4-fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)acetate

To a sealable tube charged with tert-butyl2-(4-hydroxypiperidin-1-yl)acetate (379 mg, 1.761 mmol), 18-crown-6 (233mg, 0.880 mmol), and cesium carbonate (574 mg, 1.761 mmol) in toluene(1.2 mL), was addedcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(200 mg, 0.587 mmol). The mixture was blanketed with nitrogen andsealed, and the reaction mixture was heated at 80° C. for 24 hours. Themixture was diluted with 1:2 toluene/EtOAc (6 mL), washed with brine (5mL, 2 mL), and dried over Na₂SO₄. The mixture was purified via flashchromatography using a linear gradient of 0% to 10% of 1% NH₄OH in MeOHin DCM. Intermediatecis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas collected as a tan film (172 mg).

Diamine tert-butyl2-(4-(5-amino-4-(cis-4-(isopropylcarbamoyl)cyclohexylamino)pyridin-2-yloxy)piperidin-1-yl)acetatewas prepared from tert-butyl2-(4-(4-(cis-4-(isopropylcarbamoyl)cyclohexylamino)-5-nitropyridin-2-yloxy)piperidin-1-yl)acetateusing a procedure analogous to that used to preparecis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(100 mg).

The title compound was prepared from tert-butyl2-(4-(5-amino-4-(cis-4-(isopropylcarbamoyl)cyclohexylamino)pyridin-2-yloxy)piperidin-1-yl)acetateusing a procedure analogous to that used for(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.Isolated as an off-white solid (124 mg, 79% yield, last step). M/Zcalc'd for C₃₄H₄₅FN₆O₅: 636.76. found 637 [M+H].

Example 168

2-(4-((E)-2-(4-Fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)aceticacid hydrochloride

To a solution of tert-butyl2-(4-((E)-2-(4-fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)acetate(81 mg, 0.127 mmol) in dioxane (1.2 mL) was added HCl (4N dioxane)(0.127 mL, 0.509 mmol) and 2 drops of concentrated HCl (0.010 mL, 0.127mmol). The resulting mixture was stirred at RT for 4 hours. The reactionmixture was concentrated and triturated with about 2 mL of dioxane toproduce a precipitate. The off-white solid was collected to afford thetitle compound (70 mg, 89% yield). M/Z calc'd for C₃₀H₃₇FN₆O₅: 580.28.found 581 [M+H].

Example 169

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1-methylpiperidin-4-yloxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Intermediatecis-N-isopropyl-4-(2-(1-methylpiperidin-4-yloxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamidewas prepared from 1-methylpiperidin-4-ol using a procedure analogous tothat used forcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(95 mg).

Diaminecis-4-(5-amino-2-(1-methylpiperidin-4-yloxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidewas prepared fromcis-N-isopropyl-4-(2-(1-methylpiperidin-4-yloxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a procedure analogous to that used to preparecis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(95 mg).

The title compound was prepared fromcis-4-(5-amino-2-(1-methylpiperidin-4-yloxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a procedure analogous to that used for(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. The product was isolated as an off-white solid(94 mg, 72% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, J=8H, 6H)1.48-1.78 (m, 7H) 1.84-2.03 (m, 2H) 2.04-2.10 (m, 2H) 2.13-2.34 (m, 5H)2.65 (m, 4H) 3.95-4.05 (m, 1H) 4.65-4.80 (m, 1H) 4.89-5.03 (m, 1H) 6.96(s, 1H) 7.26 (dd, J=8.75 Hz, 2H) 7.68 (d, J=7.63 Hz, 1H) 8.23 (s, 1H)8.31 (dd, J=8.56, 5.82 Hz, 2H) 12.60 (br. s., 1H). M/Z calc'd forC₂₉H₃₇FN₆O₃: 536.64. found 537 [M+H].

Example 170

(E)-4-Fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: cis-4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic acid

To a solution of cis-4-amino-1-cyclohexanecarboxylic acid (41.54 g, 290mmol) in 1 N aqueous NaOH (300 mL) was added a solution of di-tert-butyldicarbonate (76 g, 348 mmol) in dioxane (160 mL) with stirring. Thereaction was stirred at RT for 24 hours. Hexanes (400 mL) was added, andthe reaction was stirred for a further 10 minutes. After the layers wereseparated, the aqueous layer was chilled in an ice-water bath andcarefully acidified to a pH of approximately 5 with stirring by additionof 6 N aqueous HCl (50 mL). The resulting white solid was removed byfiltration, and the filtrate was extracted with EtOAc. The combinedorganic layers were washed with brine, and concentrated. The residue wasdissolved in a minimum of hot EtOAc, diluted with an equal volume ofhexanes, and allowed to stand at RT. The white precipitate was collectedby filtration, combined with the first crop of precipitate, and dried invacuo to generate cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid (87.0 g, quantitative yield).

Step B: tert-Butyl cis-4-(isopropylcarbamoyl)cyclohexylcarbamate

To a solution of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid (54.58 g, 224 mmol) in dry DMF (200 mL) was added1,1′-carbonyldiimidazole reagent grade (70 g, 432 mmol) portionwise withstirring. After the evolution of CO₂ had ceased, the resulting solutionwas stirred at RT for 10 minutes. The solution was cooled to 0° C., andisopropylamine (38.5 mL, 449 mmol) was added with stirring. The reactionwas stirred at 0° C. for 10 minutes and at RT for 24 hours. The reactionwas diluted slowly with water (1 L) with stirring in an ice-water bathand then allowed to age for 1 hour. The precipitate was collected byfiltration, washed with water, and dried in vacuo to generate tert-butylcis-4-(isopropylcarbamoyl)cyclohexyl-carbamate as a white solid (39.11g, 61% yield).

Step C: cis-4-Amino-N-isopropylcyclohexanecarboxamide hydrochloride

To a solution of tert-butylcis-4-(isopropylcarbamoyl)cyclohexylcarbamate (39.11 g, 138 mmol) in DCM(400 mL) was added 4 M HCl in dioxane (138 mL, 550 mmol), and 0.5 mLconcentrated HCl. The reaction was stirred vigorously overnight at RT. Alarge amount of white precipitate had formed in the flask and it wascollected by vacuum filtration, washed with DCM, and dried in vacuo, togenerate cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride asa white powder (31.08 g, 102% yield).

Step D:cis-4-(5-(Hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide

To a suspension of cis-4-amino-N-isopropylcyclohexanecarboxamidehydrochloride (7.09 g, 32.1 mmol) and DIPEA (15 mL, 88 mmol) in ACN (50mL) was added (3-fluoro-4-nitrophenyl)methanol (5 g, 29.2 mmol). Thereaction was stirred overnight at 80° C. The reaction mixture wasconcentrated, loaded onto a silica-gel pre column, and purified bycolumn chromatography, eluting with 0-100% EtOAc in DCM, to providecis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamideas an orange foam (7.0 g, 71.4% yield). MS, m/z (C₁₇H₂₅N₃O₄): calcd,335.2. found, 336.0 [M+H].

Step E:(E)-4-Fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution ofcis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexane-carboxamide(2.0 g, 5.96 mmol) in EtOH (25 mL) was added 10% palladium on carbon(0.635 g, 0.596 mmol). The reaction was stirred under a hydrogenatmosphere (1 atm) at RT. After 3 hours, the reaction mixture wasfiltered through Celite® brand filter aid and concentrated to affordcis-4-(2-amino-5-(hydroxymethyl)phenylamino)-N-isopropylcyclohexanecarboxamideas a brown oil.

The diamine was dissolved in THF (30 mL), cooled to 0° C., and4-fluorobenzoyl isothiocyanate (1.296 g, 7.15 mmol) was added. Thereaction mixture was stirred at 0° C. for 15 minutes, and then EDC(1.714 g, 8.94 mmol) and DIPEA (1.561 mL, 8.94 mmol) were added. Thereaction was stirred at 60° C. for 2 hours and for 16 hours at RT. Thereaction mixture was concentrated and partitioned between DCM and water.The organic layer was dried over anhydrous magnesium sulfate, filtered,concentrated, and adsorbed onto a plug of silica gel. The residualproduct was purified by column chromatography, eluting with 0-100% EtOAcin DCM, to provide(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a tan powder (2.14 g, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.76 (s, 1H), 8.33 (dd, J=5.9, 8.7 Hz, 2H), 7.62 (d, J=7.7 Hz, 1H),7.59 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz, 2H),7.18, (d, J=8.1 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 4.80 (brs, 1H), 4.55(s, 2H), 4.00-4.08 (m, 1H), 2.72-2.82 (m, 2H), 2.52 (brs, 1H), 2.11-2.19(m, 2H), 1.68-1.78 (m, 2H), 1.61-1.63 (m, 2H), 1.10 (d, J=6.6 Hz, 6H).MS, m/z (C₂₅H₂₉FN₄O₃): calcd, 452.2. found, 452.7 [M+H].

Example 171

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. (ice bath) cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was concentrated in vacuo and the residue wassuspended in ACN (2 mL) and re-concentrated to remove residual thionylchloride

The residue was resuspended in ACN (2 mL), cooled to 0° C., and2-(piperidin-4-yl)propan-2-ol (200 mg, 1.396 mmol) was added. Thereaction was stirred overnight at RT. After 16 hours, the reaction wasconcentrated, and the residue was purified by reverse-phase preparativeHPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The productfractions were combined, neutralized with saturated aqueous NaHCO₃, andextracted with EtOAc (×2). The combined organic layers were washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (77 mg, 60.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.75 (brs, 1H), 8.32 (dd, J=6.0, 8.6 Hz, 2H), 7.63 (d, J=7.7 Hz, 1H),7.57 (s, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz, 2H),7.16, (d, J=7.8 Hz, 1H), 4.84 (brs, 1H), 4.00-4.08 (m, 2H), 3.51 (brs,2H), 2.90 (brs, 2H), 2.65-2.80 (m, 2H), 2.53 (s, 1H), 2.11-2.20 (m, 2H),1.78-1.90 (m, 2H), 1.59-1.78 (m, 7H), 1.18-1.33 (m, 3H), 1.11 (d, J=6.6Hz, 6H), 1.02 (s, 6H). MS, m/z (C₃₃H₄₄FN₅O₃): calcd, 577.3. found, 578.1[M+H].

Example 172

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas suspended in ACN (2 mL) and re-concentrated to remove residualthionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and1-(methylsulfonyl)piperazine (AstaTech, Inc., Bristol, Pa.; 363 mg, 2.21mmol) was added. The reaction was stirred overnight at RT. The reactionwas concentrated, and the residue was purified by reverse-phasepreparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%).The product fractions were combined, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (74 mg, 55.9% yield). MS, m/z (C₃₀H₃₉FN₆O₄S): calcd,598.3. found, 598.8 [M+H].

Example 173

(E)-4-Fluoro-N-(6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 2-(piperazin-1-yl)ethanol, using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(30 mg, 24% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.5 Hz,6H), 1.20-1.32 (m, 1H), 1.55-1.83 (m, 5H), 2.09-2.21 (m, 2H), 2.28-2.45(m, 6H), 2.54 (br. s, 1H), 2.64-2.82 (m, 2H), 3.44-3.66 (m, 5H),3.96-4.12 (m, 1H), 4.38 (br. s., 1H), 4.86 (br. s., 1H), 7.14 (d, J=8.3Hz, 1H), 7.24 (dd, J=8.4 Hz, 8.4 Hz, 2H), 7.48 (d, J=8.2 Hz, 1H), 7.59(br. s., 1H), 7.64 (d, J=7.2 Hz, 1H), 8.32 (m, J=6.5 Hz, 2H), 12.74 (br.s., 1H). MS, m/z (C₃₁H₄₁FN₆O₃): calcd, 564.3. found, 564.9 [M+H].

Example 174

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand piperazine using a method analogous to that used in the preparationof(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(58 mg, 50% yield). MS, m/z (C₂₉H₃₇FN₆O₂): calcd, 520.3. found, 521.1[M+H].

Example 175

(S)-1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand (S)-pyrrolidine-2-carboxamide using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(41 mg, 34% yield). MS, m/z (C₃₀H₃₇FN₆O₃): calcd, 548.3. found, 549.0[M+H].

Example 176

(R)-1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-2-carboxamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand (R)-pyrrolidine-2-carboxamide using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(47 mg, 39% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.6 Hz,6H), 1.51-1.79 (m, 5H), 2.07-2.19 (m, 2H), 2.40 (br. s., 4H), 2.53 (br.s., 1H), 2.60-2.79 (m, 2H), 2.85 (br. s., 4H), 3.54 (s, 2H), 3.96-4.10(m, 1H), 4.80-4.92 (m, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.8 Hz,8.8 Hz, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.56-7.74 (m, 2H), 8.31 (dd, J=8.1,6.1 Hz, 2H). MS, m/z (C₃₀H₃₇FN₆O₃): calcd, 548.3. found, 549.0 [M+H].

Example 177

1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand piperidine-4-carboxamide using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(57 mg, 46% yield). MS, m/z (C₃₁H₃₉FN₆O₃): calcd, 562.3. found, 563.1[M+H].

Example 178

(E)-4-Fluoro-N-(6-((2-hydroxy-2-methylpropylamino)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 1-amino-2-methylpropan-2-ol using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(33 mg, 29% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.15 (m, 12H),1.23-1.28 (m, 2H), 1.56-1.79 (m, 5H), 2.09-2.17 (m, 2H), 2.45 (br. s.,1H), 2.53 (br. s., 1H), 2.72-2.87 (m, 2H), 3.87 (br. s., 2H), 3.99-4.10(m, 1H), 4.86 (br. s, 1H), 7.19-7.28 (m, 3H), 7.49 (d, J=8.2 Hz, 1H),7.60-7.70 (m, 2H), 8.32 (dd, J=8.6, 5.8 Hz, 2H), 12.75 (s, 1H). MS, m/z(C₂₉H₃₈FN₅O₃): calcd, 523.3. found, 524.1 [M+H].

Example 179

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((3-oxopiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide2,2,2-trifluoroacetate

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide and piperazine-2-one using a method analogous tothat used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(72 mg, 50% yield). MS, m/z (C₂₉H₃₅FN₆O₃.C₂HF₃O₂): calcd, 534.3. found,535.4 [M+H].

Example 180

1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-3-carboxamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand piperidine-3-carboxamide using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(6 mg, 4% yield). MS, m/z (C₃₁H₃₉FN₆O₃): calcd, 562.3. found, 563.1[M+H].

Example 181

1-(((E)-2-(4-Fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-sulfonicacid

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand piperidine-4-sulfonic acid using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(24 mg, 18% yield). MS, m/z (C₃₀H₃₈FN₅O₅S): calcd, 599.3. found, 599.7[M+H].

Example 182

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(morpholine-4-carbonyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand morpholino(piperidin-4-yl)methanone hydrochloride using a methodanalogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide,with a reaction temperature of 50° C. for 4 hours. The title compoundwas isolated as a white powder (49 mg, 35.0% yield). MS, m/z(C₃₅H₄₅FN₆O₄): calcd, 632.4. found, 633.0 [M+H].

Example 183

(E)-4-Fluoro-N-(6-((4-hydroxy-4-methylpiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 4-methylpiperidin-4-ol using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide.The title compound was isolated as a white powder (37 mg, 30% yield).MS, m/z (C₃₁H₄₀FN₅O₃): calcd, 549.3. found, 549.9 [M+H].

Example 184

(E)-4-Fluoro-N-(6-O(S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed at reduced pressure,and the residue was suspended in ACN (2 mL) and re-concentrated toremove residual thionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and(S)-2-(pyrrolidin-2-yl)propan-2-ol hydrochloride (183 mg, 1.105 mmol)and sodium hydride (60% dispersion in mineral oil, 44 mg, 1.105 mmol)were added. The reaction was stirred at RT for 16 hours. The reactionwas concentrated, and the residue was purified by reverse-phasepreparative HPLC, using 0.1% TFA in ACN/water (gradient 15% to 90%). Theproduct fractions were combined, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-4-fluoro-N-(6-(((S)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a purple powder (44 mg, 35.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.09 (dd, J=6.6, 1.6 Hz, 6H), 1.14 (s, 6H), 1.55-1.81 (m, 8H), 2.04-2.11(m, 2H), 2.19-2.28 (m, 1H), 2.54 (br. s, 1H), 2.62-2.68 (m, 1H),2.76-2.90 (m, 3H), 3.51 (d, J=14.4 Hz, 1H), 3.98-4.09 (m, 1H), 4.14 (s,1H), 4.36 (d, J=13.3 Hz, 1H), 4.86-4.96 (m, 1H), 7.18 (d, J=8.0 Hz, 1H),7.22-7.29 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.79(s, 1H), 8.30 (dd, J=8.9, 5.9 Hz, 2H), 12.71 (s, 1H). MS, m/z(C₃₂H₄₂FN₅O₃): calcd, 563.3. found, 564.0 [M+H].

Example 185

(E)-4-Fluoro-N-(6-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: Benzyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

To a solution of benzyl piperazine-1-carboxylate (0.5 g, 2.270 mmol) andTEA (0.949 mL, 6.81 mmol) in THF (10 mL) was added methyl 2-bromoacetate(0.230 mL, 2.497 mmol) dropwise. The reaction was stirred at 65° C.After 1 hour, the reaction mixture was concentrated, and the residue waspartitioned between EtOAc and saturated aqueous NaHCO₃. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated to generate benzyl4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as a clear oil (0.61 g,92% yield).

Step B: Benzyl 4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate

To a solution of benzyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate(0.61 g, 2.087 mmol) in THF (5 mL) at 0° C. was added methylmagnesiumiodide (2.087 mL, 6.26 mmol) dropwise. The reaction was stirred atambient temperature for 10 minutes then stirred at 35° C. for 3 hours,and overnight at ambient temperature. The reaction was quenched withsaturated aqueous ammonium chloride and extracted with EtOAc. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide benzyl4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate as a yellow oil(0.54 g, 89% yield). MS, m/z (C₁₆H₂₄N₂O₃): calcd, 292.2. found, 293.1[M+H].

Step C: 2-Methyl-1-(piperazin-1-yl)propan-2-ol dihydrochloride

To a solution of benzyl4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate (0.54 g, 1.847mmol) in EtOH (10 mL) was added 10% palladium on carbon (0.1 g, 0.094mmol). The reaction was stirred overnight under a hydrogen atmosphere.After 16 hours, the reaction was filtered through Celite® brand filteraid (rinsed with MeOH and DCM). The filtrate was concentrated to a clearoil, the oil was diluted with EtOAc, and 4 N HCl/dioxane (0.5 mL; 2mmol) was added dropwise. The white precipitate was collected by vacuumfiltration, washed with diethyl ether, and dried in vacuo, to generate2-methyl-1-(piperazin-1-yl)propan-2-ol hydrochloride as a brown powder(0.31 g, 86% yield).

Step D:(E)-4-Fluoro-N-(6-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas suspended in ACN (2 mL) and re-concentrated to remove residualthionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and2-methyl-1-(piperazin-1-yl)propan-2-ol dihydrochloride (153 mg, 0.663mmol) and TEA (0.25 mL, 1.77 mmol) were added. The reaction was stirredfor 16 hours at RT then 4 hours at 50° C. The reaction was concentrated,and the residue was redissolved in 2 mL MeOH. The residual material waspurified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water(gradient 15% to 90%). The product fractions were combined, neutralizedwith saturated aqueous NaHCO₃, and extracted with EtOAc (×2). Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The product was furtherpurified by column chormatography, eluting with 0-100% (90:9:1)DCM/MeOH/NH₄OH in DCM, to provide(E)-4-fluoro-N-(6-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas an off-white powder (26 mg, 19.9% yield). MS, m/z (C₃₃H₄₅FN₆O₃):calcd, 592.3. found, 593.0 [M+H].

Example 186

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-6-((4-(2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: tert-Butyl4-(2,2,2-trifluoro-1-(trimethylsilyloxy)ethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (AstaTechInc., Bristol, Pa.; 1 g, 4.69 mmol) in THF (10 mL) at 0° C. was addedtrimethyl(trifluoromethyl)silane (0.832 mL, 5.63 mmol) and TBAF (1 dropof a 1M solution in THF). The reaction was allowed to warm to RT andstirred for 2 hours. The reaction was diluted with diethyl ether andwashed with 1 N aqueous HCl and brine. The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated to yieldtert-butyl4-(2,2,2-trifluoro-1-(trimethylsilyloxy)ethyl)piperidine-1-carboxylateas a yellow oil which crystallized upon standing (1.62 g, 97% yield).

Step B: 2,2,2-Trifluoro-1-(piperidin-4-yl)ethanol hydrochloride

To a solution of tert-butyl4-(2,2,2-trifluoro-1-(trimethylsilyloxy)ethyl)piperidine-1-carboxylate(1.6 g, 4.50 mmol) in DCM (9 mL) and MeOH (1 mL) was added 2 M HCl inether (11.25 mL, 22.51 mmol). The reaction was stirred at RT for 16hours. The precipitate that formed was collected by vacuum filtration,washed with diethyl ether, and dried in vacuo to generate2,2,2-trifluoro-1-(piperidin-4-yl)ethanol hydrochloride as a whitepowder (0.83 g, 84% yield).

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-6-((4-(2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed at reduced pressure,and the residue was suspended in ACN (2 mL) and re-concentrated toremove residual thionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and2,2,2-trifluoro-1-(piperidin-4-yl)ethanol hydrochloride (146 mg, 0.663mmol) and DBU (0.133 mL, 0.884 mmol) were added. The reaction wasstirred for 48 hours at RT, and then the reaction was concentrated andthe residue was purified by reverse-phase preparative HPLC, using 0.1%TFA in ACN/water, (gradient 15% to 90%). The product fractions werecombined, neutralized with saturated aqueous NaHCO₃, and extracted withEtOAc (×2). The combined organic layers were washed with brine, driedover anhydrous magnesium sulfate, filtered, and concentrated to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-6-((4-(2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (56 mg, 41.0% yield). MS, m/z (C₃₂H₃₉F₄N₅O₃): calcd,617.3. found, 618.0 [M+H].

Example 187

N,N-Diethyl-N-(((E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)ethanaminiumchloride

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed at reduced pressure,and the residue was suspended in ACN (2 mL) and re-concentrated toremove residual thionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and2,2,2-trifluoro-1-(piperidin-4-yl)ethanol hydrochloride (146 mg, 0.663mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction wasstirred for 48 hours at RT, followed by 4 hours at 50° C. The reactionwas concentrated, and the residue was purified by reverse-phasepreparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%).The product fractions were combined, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide N,N-diethyl-N-4(E)-2-(4-fluorobenzoylimino)-3-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)ethanaminiumchloride as an off-white powder (76 mg, 60.1% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10 (d, J=6.7 Hz, 6H), 1.36 (t, J=7.1 Hz, 9H), 1.59-1.83(m, 4H), 2.01-2.09 (m, 2H), 2.56 (br. s, 1H), 2.71-2.89 (m, 2H), 3.22(q, J=7.2 Hz, 6H), 3.92-4.02 (m, 1H), 4.54 (s, 2H), 4.86-5.04 (m, 1H),7.27 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.2Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.88 (s, 1H), 8.32 (dd, J=8.9, 5.8 Hz,2H), 12.94 (s, 1H). MS, m/z (C₃₁H₄₃FN₅O₂.Cl): calcd, 536.3. found, 536.1[M+H].

Example 188

(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: tert-Butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate

To a solution of 1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate (900mg, 4.18 mmol) in THF (25 mL) at 0° C. was added 3 M methylmagnesiumiodide in ether (4.18 mL, 12.54 mmol) dropwise. The reaction was stirredovernight at RT. The reaction was quenched with saturated aqueousammonium chloride and extracted with EtOAc. The organic layer wasconcentrated, adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 20-100% (90:9:1 DCM/MeOH/NH₄OH)/DCM, toprovide tert-butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate as ayellow oil (867 mg, 96% yield).

Step B: 2-(Azetidin-3-yl)propan-2-ol hydrochloride

To a solution of tert-butyl3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate (0.87 g, 4.04 mmol) inDCM (15 mL) at 0° C. was added 4 M HCl in dioxane (8.08 mL, 16.16 mmol)dropwise. The reaction was stirred overnight at RT. The reaction mixturewas concentrated and dried in vacuo to generate2-(azetidin-3-yl)propan-2-ol hydrochloride as a brown solid (0.44 g,71.8% yield).

Step C:(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed on a rotovap, and the residue suspendedin ACN (2 mL) and re-concentrated to remove residual thionyl chloride.The residue was resuspended in DMF (2 mL), cooled to 0° C., and2-(azetidin-3-yl)propan-2-ol hydrochloride (101 mg, 0.663 mmol) and DBU(0.10 mL, 0.663 mmol) were added. After stirring for 16 hours at RT, thereaction mixture was concentrated and purified by reverse-phasepreparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%).The product fractions were combined, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)as a white powder benzamide (26 mg, 21.4% yield). MS, m/z (C₃₁H₄₀FN₅O₃):calcd, 549.3. found, 549.9 [M+H].

Example 189

(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: tert-Butyl 3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate

To a solution of 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate(0.98 g, 4.27 mmol) in diethyl ether (5 mL) at 0° C. was added 3 Mmethylmagnesium iodide in ether (4.27 mL, 12.82 mmol) dropwise. A largeamount of precipitate formed, so THF (5 mL) was added to improve thesolubility. The reaction was stirred at RT for 10 minutes and thenstirred at reflux for 3 hours, and at RT for 16 hours. The reaction wasquenched with saturated aqueous ammonium chloride and extracted withEtOAc. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated to provide tert-butyl3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate as a yellow oil (0.69g, 70.4% yield).

Step B: 2-(Pyrrolidin-3-yl)propan-2-ol hydrochloride

To a solution of tert-butyl3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate (0.69 g, 3.01 mmol) inDCM (15 mL) and EtOAc (5 mL) was added 4 M HCl in dioxane (3.01 mL,12.04 mmol). The reaction was stirred overnight at RT and thenconcentrated to generate 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride asa yellow oil (0.51 g, 102% yield).

Step C:(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas suspended in ACN (2 mL) and re-concentrated to remove residualthionyl chloride. The residue was resuspended in ACN (2 mL), cooled to0° C., and 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (110 mg, 0.663mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction wasstirred for 16 hours at RT, followed by 4 hours at 50° C. and 6 hours at80° C. The reaction was cooled to RT, DBU (0.17 mL, 1.105 mmol) wasadded, and the reaction was stirred overnight at 40° C. The reaction wasconcentrated, adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH₄OH)/DCM, toprovide(E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a light-yellow powder (65 mg, 52.2% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.03 (s, 6H), 1.11 (d, J=6.7 Hz, 6H), 1.54-1.79 (m, 7H), 2.09-2.19(m, 3H), 2.36 (br. s., 2H), 2.52 (br. s., 1H), 2.59 (br. s., 1H),2.69-2.84 (m, 2H), 3.55 (br. s., 1H), 3.68 (br. s., 1H), 3.99-4.10 (m,2H), 4.83 (br. s., 1H), 7.14-7.19 (m, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz,2H), 7.48 (d, J=8.0 Hz, 1H), 7.55-7.66 (m, 2H), 8.32 (dd, J=8.7, 6.0 Hz,2H), 12.74 (br. s., 1H). MS, m/z (C₃₂H₄₂FN₅O₃): calcd, 563.3. found,564.0 [M+H].

Example 190

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-((2,2,2-trifluoroethylamino)methyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: tert-Butyl4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69mmol) in DCM (25 mL) was added 2,2,2-trifluoroethanamine (0.464 g, 4.69mmol) and AcOH (0.05 mL). The reaction was stirred at RT for 3 hours andthen sodium triacetoxyborohydride (1.292 g, 6.10 mmol) was added, andthe reaction was stirred at RT for 16 hours. The reaction was dilutedwith DCM and saturated aqueous NaHCO₃. The aqueous layer was adjusted toa pH of approximately 10 with 1 N aqueous NaOH, and extracted with DCM.The combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated to generate tert-butyl4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate as acolorless oil (1.49 g, 107% yield).

Step B: 2,2,2-Trifluoro-N-(piperidin-4-ylmethyl)ethanaminedihydrochloride

To a solution of tert-butyl4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate (1.49 g,5.03 mmol) in DCM (25 mL) was added 4 N HCl in dioxane (5.03 mL, 20.11mmol). The reaction was stirred at RT. After 16 hours, the whiteprecipitate was collected by vacuum filtration, washed with diethylether, and dried in vacuo, to generate2,2,2-trifluoro-N-(piperidin-4-ylmethyl)ethanamine dihydrochloride as awhite powder (1.07 g, 3.98 mmol, 79% yield).

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-((2,2,2-trifluoroethylamino)methyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas suspended in ACN (2 mL) and re-concentrated to remove residualthionyl chloride.

The residue was resuspended in ACN (2 mL), cooled to 0° C., and2,2,2-trifluoro-N-(piperidin-4-ylmethyl)ethanamine dihydrochloride (178mg, 0.663 mmol) and DBU (0.233 mL, 1.547 mmol) were added. The reactionwas stirred for 3 days at RT, and then the reaction was concentrated andthe residual material was purified by reverse-phase preparative HPLC,using 0.1% TFA in ACN/water, (gradient 15% to 75%). The productfractions were combined, neutralized with saturated aqueous NaHCO₃, andextracted with EtOAc (×2). The combined organic layers were washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-((2,2,2-trifluoroethylamino)methyl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (35 mg, 25.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.11 (d, J=1.0 Hz, 6H), 1.16-1.27 (m, 2H), 1.33 (br. s., 1H), 1.56-1.77(m, 6H), 1.91 (br. s., 2H), 2.05-2.33 (m, 4H), 2.53 (br. s., 1H),2.65-2.93 (m, 4H), 3.09-3.24 (m, 3H), 3.52 (br. s., 2H), 3.94-4.16 (m,1H), 4.86 (br. s., 1H), 7.14 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.8 Hz, 2H),7.48 (d, J=8.2 Hz, 1H), 7.56-7.65 (m, 2H), 8.31 (dd, J=8.3, 6.2 Hz, 2H),12.73 (br. s., 1H). MS, m/z (C₃₃H₄₂F₄N₆O₂): calcd, 630.3. found, 631.2[M+H].

Example 191

(E)-N-(6-((4,4-Difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed, and the residue was resuspended in 2mL DMSO, cooled to 0° C., and 4,4-difluoropiperidine hydrochloride (348mg, 2.210 mmol) and TEA (0.308 mL, 2.210 mmol) were added. The reactionwas stirred for 30 minutes at 0° C. and then at RT for 16 hours. Thereaction was concentrated, and the residue was purified by reverse-phasepreparative HPLC, using 0.1% TFA in AC/water (gradient 15% to 90%). Theproduct fractions were combined, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide(E)-N-(6-((4,4-difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideas a white powder (71 mg, 57.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.11 (s, 6H), 1.54-1.83 (m, 5H), 1.94-2.18 (m, 7H), 2.53 (br. s., 3H),2.67-2.86 (m, 2H), 3.64 (s, 2H), 3.94-4.09 (m, 1H), 4.91 (br. s., 1H),7.13 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.49 (d, J=8.1Hz, 1H), 7.60-7.82 (m, 2H), 8.20-8.43 (m, 2H), 12.75 (br. s., 1H). MS,m/z (C₃₀H₃₆F₃N₅O₂): calcd, 555.3. found, 555.9 [M+H].

Example 192

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methoxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed and the residue was resuspended in ACN(2 mL), cooled to 0° C., and sodium methoxide (478 mg, 2.210 mmol) wasadded. The reaction was stirred overnight at RT. The solvent was removedon a rotovap, and the residue was partitioned between water and DCM. Theaqueous layer was neutralized (pH approximately 8) with concentrated HCland extracted with DCM. The combined organic layers were concentrated,adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 0-10% MeOH in DCM, to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methoxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (45 mg, 43.6% yield). MS, m/z (C₂₆H₃₁FN₄O₃): calcd,466.2. found, 466.8 [M+H].

Example 193

N-((2E)-6-((1,1-Dioxido-4-thiomorpholinyl)methyl)-1-(cis-4-((1-methylethyl)carbamoyl)cyclohexyl)-1,3-dihydro-2H-benzimidazol-2-ylidene)-4-fluorobenzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand thiomorpholine-1,1-dioxide using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-44-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(67 mg, 53% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.75 (s, 1H), 8.31(dd, J=6.2, 8.7 Hz, 2H), 7.80 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.49 (d,J=8.2 Hz, 1H), 7.25 (dd, J=8.6 Hz, 8.6 Hz, 2H), 7.13, (d, J=8.6 Hz, 1H),4.86-4.97 (m, 1H), 4.00-4.07 (m, 1H), 3.76 (s, 2H), 3.22 (brs, 4H), 2.92(brs, 4H), 2.75-2.84 (m, 2H), 2.54 (brs, 1H), 2.05-2.14 (m, 2H),1.69-1.79 (m, 2H), 1.59-1.65 (m, 2H), 1.11 (d, J=6.6 Hz, 6H). MS, m/z(C₂₉H₃₆FN₅O₄S): calcd, 569.3. found, 569.7 [M+H].

Example 194

(E)-N-(6-((1H-1,2,4-Triazol-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas dried in vacuo for 5 minutes. The residue was resuspended in ACN (2mL), cooled to 0° C., and 1H-1,2,4-triazole (153 mg, 2.210 mmol),potassium carbonate (305 mg, 2.210 mmol), and sodium iodide (33.1 mg,0.221 mmol) were added. The reaction was stirred at RT. After 16 hours,the solvent was removed, and the residue was partitioned between waterand DCM. The aqueous layer was neutralized (pH approximately 8) with 2 Naqueous HCl and extracted with DCM. The combined organic layers wereconcentrated, adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 0-10% MeOH in DCM, to provide(E)-N-(6-((1H-1,2,4-triazol-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(35 mg, 31% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.80 (s, 1H), 8.69(s, 1H), 8.33 (dd, J=6.0, 8.6 Hz, 2H), 7.95 (s, 1H), 7.76 (s, 1H), 7.67(d, J=7.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz,2H), 7.15, (d, J=8.2 Hz, 1H), 5.45 (s, 2H), 4.78 (brs, 1H), 4.02-4.14(m, 1H), 2.74-2.85 (m, 2H), 2.54 (brs, 1H), 2.10-2.13 (d, J=12.8 Hz,2H), 1.69-1.76 (m, 2H), 1.59-1.62 (m, 2H), 1.11 (d, J=6.6 Hz, 6H). MS,m/z (C₂₇H₃₀FN₇O₂): calcd, 503.2. found, 503.7 [M+H].

Example 195

(E)-N-(6-((4H-1,2,4-Triazol-4-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was isolated from the reaction to prepare(E)-N-(6-((1H-1,2,4-triazol-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(17 mg, 15% yield). MS, m/z (C₂₇H₃₀FN₇O₂): calcd, 503.2. found, 503.7[M+H].

Example 196

(E)-N-(6-((3,3-Difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. The solvent was removed at reduced pressure, and the residuewas dried in vacuo for 5 minutes. The residue was resuspended in ACN (1mL) and cooled to 0° C. A suspension of 3,3-difluoropyrrolidinhydrochloride (317 mg, 2.210 mmol) and sodium hydride (88 mg, 2.210mmol) in ACN (1 mL) was added, and the reaction was stirred overnight atRT. The solvent was removed at reduced pressure, and the residue wasredissolved in 2 mL of MeOH. The residual material was purified byreverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient15% to 90%). The product fractions were combined, neutralized withsaturated aqueous NaHCO₃, and extracted with EtOAc (×2). The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated to provide(E)-N-(6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideas a white powder (59 mg, 49.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.77 (s, 1H), 8.32 (s, 2H), 7.63 (brs, 2H), 7.50 (d, J=7.3 Hz, 1H),7.24 (brs, 2H), 7.15, (d, J=8.0 Hz, 1H), 4.87 (brs, 1H), 4.02-4.05 (m,1H), 3.69 (s, 2H), 2.89 (t, J=13.1 Hz, 2H), 2.71-2.77 (m, 4H), 2.53(brs, 1H), 2.27 (m, 2H), 2.12-2.15 (m, 2H), 1.62-1.73 (m, 4H), 1.10 (d,J=5.6 Hz, 6H). MS, m/z (C₂₉H₃₄F₃N₅O₂): calcd, 541.3. found, 541.8 [M+H].

Example 197

(E)-N-(6-((1H-Pyrazol-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 1H-pyrazole using a method analogous to that used in the preparationof(E)-N-(6-(93,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(23 mg, 21% yield). MS, m/z (C₂₈H₃₁FN₆O₂): calcd, 502.2. found, 502.8[M+H].

Example 198

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((2-methoxyethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 2-methoxyethanol using a method analogous to that used in thepreparation of(E)-N-(6-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide(14 mg, 12% yield). MS, m/z (C₂₈H₃₅FN₄O₄): calcd, 510.2. found, 510.9[M+H].

Example 199

(E)-4-Fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

The title compound was prepared from cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateand morpholine using a method analogous to that used in the preparationof(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(2.34 g, quantitative yield). MS, m/z (C₂₇H₃₁FN₄O₄): calcd, 494.2.found, 495.0 [M+H].

Step B:cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid

To a suspension of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(2.3 g, 4.65 mmol) in MeOH (46.5 mL) was added 1 N aqueous sodiumhydroxide (46.5 mL, 46.5 mmol). The suspension was stirred overnight atRT. The resulting solution was concentrated, adjusted to a pH ofapproximately 4 with 2 N aqueous HCl, and extracted with DCM. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated to generatecis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid as a white powder (2.29 g, 102% yield). MS, m/z (C₂₆H₂₉FN₄O₄):calcd, 480.2. found, 480.2 (M).

Step C:cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride

To a 0° C. suspension ofcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (0.5 g, 1.041 mmol) in DCM (10.41 mL) was added thionyl chloride(0.380 mL, 5.20 mmol). The suspension was stirred for 30 minutes at 0°C. The reaction was concentrated, resuspended in ACN (5 mL), andreconcentrated to generatecis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride (0.50 g, 96% yield) as a white powder.

Step D:(E)-4-Fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. suspension ofcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride (50 mg, 0.100 mmol) in THF (1 mL) was added2-amino-2-methylpropan-1-ol (17.8 mg, 0.401 mmol). The mixture wasstirred for 1 hour at RT. The solvent was removed, and the residue waspurified by reverse-phase preparative HPLC, using 0.1% NH₄OH inACN/water. The product fractions were combined and concentrated toprovide(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (8.5 mg, 15.4% yield). MS, m/z (C₃₀H₃₈FN₅O₄): calcd,551.3. found, 552.4 [M+H].

Example 200

(E)-4-Fluoro-N-(1-(cis-4-((R)-1-hydroxypropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and (R)-2-aminopropan-1-ol using a method analogous to thatused in the preparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(26.5 mg, 49% yield). MS, m/z (C₂₉H₃₆FN₅O₄): calcd, 537.3. found, 538.4[M+H].

Example 201

(E)-4-Fluoro-N-(1-(cis-4-(2-hydroxyethylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and 2-aminoethanol using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(25.3 mg, 48% yield). MS, m/z (C₂₈H₃₄FN₅O₄): calcd, 523.3. found, 524.3[M+H].

Example 202

(E)-4-Fluoro-N-(1-(cis-4-(morpholine-4-carbonyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and morpholine using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(7.4 mg, 13% yield). MS, m/z (C₃₀H₃₆FN₅O₄): calcd, 549.3. found, 550.4[M+H].

Example 203

(E)-4-Fluoro-N-(1-(cis-4-(4-methylpiperazine-1-carbonyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and 1-methylpiperazine using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(15.2 mg, 27% yield). MS, m/z (C₃₁H₃₉FN₆O₃): calcd, 562.3. found, 563.4[M+H].

Example 204

(E)-4-Fluoro-N-(6-(morpholinomethyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and piperazine using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(3.8 mg, 7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63 (d, J=11.5 Hz,2H), 1.73-1.84 (m, 2H), 1.95-2.03 (m, 2H), 2.39 (br. s., 4H), 2.73 (br.s., 4H), 2.79-2.94 (m, 2H), 3.03 (br. s., 1H), 3.46 (br. s., 2H),3.51-3.65 (m, 9H), 4.83 (br. s., 1H), 7.15 (d, J=8.2 Hz, 1H), 7.24 (dd,J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.68 (s, 1H), 8.33 (dd,J=8.6, 5.8 Hz, 2H). MS, m/z (C₃₀H₃₇FN₆O₃): calcd, 548.3. found, 549.4[M+H].

Example 205

(E)-N-(1-(cis-4-Carbamoylcyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and 1 M ammonia in MeOH using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(19.5 mg, 40% yield). MS, m/z (C₂₆H₃₀FN₅O₃): calcd, 479.2. found, 480.2[M+H].

Example 206

(E)-4-Fluoro-N-(1-(cis-4-(2-hydroxy-2-methylpropylcarbamoyl)-cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and 1-amino-2-methylpropan-2-ol using a method analogous tothat used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(26.4 mg, 48% yield). MS, m/z (C₃₀H₃₈FN₅O₄): calcd, 551.3. found, 552.4[M+H].

Example 207

(E)-4-Fluoro-N-(1-(cis-4-(hydroxycarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and hydroxylamine using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(12.5 mg, 25% yield). MS, m/z (C₂₆H₃₀FN₅O₄): calcd, 495.2. found, 496.2[M+H].

Example 208

(E)-4-Fluoro-N-(1-(cis-4-(methoxycarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonylchloride and O-methylhydroxylamine using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(27.4 mg, 54% yield). MS, m/z (C₂₇H₃₂FN₅O₄): calcd, 509.2. found, 510.2[M+H].

Example 209

cis-Methyl4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

To a 0° C. cooled solution of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(1 g, 2.350 mmol) in DCM (25 mL) was added thionyl chloride (0.858 mL,11.75 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed at reduced pressure,and the residue was suspended in ACN (5 mL) and re-concentrated toremove residual thionyl chloride. The residue was resuspended in ACN (15mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (1.010 g, 7.05mmol) and TEA (0.655 mL, 4.70 mmol) were added. The reaction was stirredovernight at RT. After 16 hours, the reaction mixture was concentratedand partitioned between EtOAc and water. The organic layer wasconcentrated and the residual product was purified by columnchromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH₄OH)/DCM toprovide cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylateas a white powder (1.05 g, 81% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.03 (s, 6H), 1.09-1.35 (m, 3H), 1.56-1.91 (m, 8H), 2.21-2.29 (m, 2H),2.53-2.64 (m, 2H), 2.77-2.95 (m, 3H), 3.50 (s, 2H), 3.77 (s, 3H), 3.99(s, 1H), 4.74 (br. s., 1H), 7.14 (d, J=6.9 Hz, 1H), 7.26 (dd, J=8.8 Hz,8.8 Hz, 2H), 7.37-7.58 (m, 2H), 8.26 (dd, J=8.7, 5.9 Hz, 2H), 12.77 (s,1H). MS, m/z (C₃₁H₃₉FN₄O₄): calcd, 550.3. found, 551.1 [M+H].

Example 210

cis-4-((E)-2-(4-Fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid

To a solution of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(1.05 g, 1.907 mmol) in MeOH (20 mL) was added 1 N aqueous NaOH (19.07mL, 19.07 mmol). The solution was stirred overnight at RT. After 2 days,the reaction solution was concentrated, the pH was adjusted to 4 with 2N aqueous HCl, and the mixture was extracted with 9:1 DCM/2-propanol.The organic layer was dried over anhydrous magnesium sulfate, filtered,and concentrated to generatecis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (1.01 g, 1.882 mmol, 99% yield) as a white powder. MS, m/z(C₃₀H₃₇FN₄O₄): calcd, 536.3. found, 537.0 [M+H].

Example 211

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a suspension ofcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid (100 mg, 0.186 mmol) in DMF (3 mL) was added HATU (74.4 mg, 0.196mmol) and DIPEA (0.036 mL, 0.205 mmol). The suspension was stirred for15 minutes at RT. A solution of piperazine (161 mg, 1.863 mmol) in DMF(1 mL) was added, and the reaction was stirred at RT overnight. Thereaction mixture was partitioned between water and EtOAc. The organiclayer was concentrated and the residue purified by HPLC (15-90% ACN/0.1%TFA). The product fractions were combined, neutralized with saturatedaqueous NaHCO₃, and extracted with EtOAc (×2). The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated to provide(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (67 mg, 59.5% yield). MS, m/z (C₃₄H₄₅FN₆O₃): calcd,604.3. found, 605.1 [M+H].

Example 212

(E)-N-(1-(cis-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and 0.5-M ammonia in dioxane using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(68 mg, 68% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (s, 6H),1.20-1.35 (m, 3H), 1.55-1.78 (m, 6H), 1.78-1.90 (m, 2H), 2.16-2.24 (m,2H), 2.55 (br. s., 1H), 2.71-2.94 (m, 4H), 3.50 (br. s., 2H), 4.01 (s,1H), 4.76 (br. s., 1H), 6.91 (br. s., 1H), 7.16 (d, J=7.6 Hz, 1H), 7.29(dd, J=8.9 Hz, 8.9 Hz, 2H), 7.35 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.55(s, 1H), 8.29 (dd, J=8.7, 6.1 Hz, 2H), 12.73 (br. s., 1H). MS, m/z(C₃₀H₃₈FN₅O₃): calcd, 535.3. found, 536.1 [M+H].

Example 213

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(methoxycarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and O-methylhydroxylamine hydrochloride using a method analogous tothat used in the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(76 mg, 72% yield). MS, m/z (C₃₁H₄₀FN₅O₄): calcd, 565.3. found, 566.1[M+H].

Example 214

(E)-4-Fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and 2-amino-2-methylpropan-1-ol using a method analogous to thatused in the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(76 mg, 72% yield). MS, m/z (C₃₄H₄₆FN₅O₄): calcd, 607.3. found, 608.1[M+H].

Example 215

(E)-N-(1-(cis-4-(tert-Butylcarbamoyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and 2-methylpropan-2-amine using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(88 mg, 80% yield). MS, m/z (C₃₄H₄₆FN₅O₃): calcd, 591.4. found, 592.1[M+H].

Example 216

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperidine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and piperidine using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(80 mg, 71% yield). MS, m/z (C₃₅H₄₆FN₅O₃): calcd, 603.4. found, 604.1[M+H].

Example 217

(E)-N-(1-(cis-4-(3,8-Fiazabicyclo[3.2.1]octane-8-carbonyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamidedihydrochloride Step A: tert-Butyl8-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate using amethod analogous to that used in the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(70 mg, 51% yield). MS, m/z (C₄₁H₅₅FN₆O₅): calcd, 730.4. found, 731.1[M+H].

Step B:(E)-N-(1-(cis-4-(3,8-Diazabicyclo[3.2.1]octane-8-carbonyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamidedihydrochloride

To a solution of tert-butyl8-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(70 mg, 0.096 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.120mL, 0.479 mmol). The suspension was stirred overnight at RT. After 16hours, the reaction was concentrated to provide(E)-N-(1-(cis-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamidedihydrochloride as a white powder (68 mg, 101% yield). MS, m/z(C₃₆H₄₇FN₆O₃.2HCl): calcd, 630.4. found, 631.2 [M+H].

Example 218

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A:cis-4-(5-Chloro-2-nitrophenylamino)-N-isopropylcyclohexane-carboxamide

To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamidehydrochloride (2.5 g, 11.33 mmol) and DIPEA (5.93 mL, 34.0 mmol) in ACN(25.2 mL) was added 4-chloro-2-fluoro-1-nitrobenzene (1.988 g, 11.33mmol). The reaction mixture was stirred overnight at 80° C. After 16hours, the reaction mixture was concentrated, and a large amount ofyellow crystals formed in the flask. The crystals were collected byvacuum filtration, washed with ether, and dried in vacuo to generate 2.5g of clean product. The filtrate was concentrated, and the residue waspurified by column chromatography, eluting with 0-50% EtOAc in DCM, toprovide an additional 0.84 g of product as a yellow powder, which wascombined with the crystals to affordcis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexane-carboxamide(3.33 g, 87% yield).

Step B:cis-N-Isopropyl-4-(5-morpholino-2-nitrophenylamino)-cyclohexanecarboxamide

A suspension ofcis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(300 mg, 0.883 mmol) in morpholine (2 mL, 22.93 mmol) was irradiated ina microwave reactor for 1 hour at 150° C. The reaction mixture waspartitioned between water and DCM. The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated to a yellow oil.The residue was concentrated, adsorbed onto a plug of silica gel, andpurified by column chromatography, eluting with 0-100% EtOAc in DCM, toprovidecis-N-isopropyl-4-(5-morpholino-2-nitrophenylamino)cyclohexanecarboxamideas a yellow powder (0.38 g, 110% yield). MS, m/z (C₂₀H₃₀N₄O₄): calcd,390.2. found, 390.9 [M+H].

Step C:cis-4-(2-Amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide

To a suspension ofcis-N-isopropyl-4-(5-morpholino-2-nitrophenylamino)cyclohexanecarboxamide(380 mg, 0.973 mmol) in EtOH (10 mL) was added ammonium formate (614 mg,9.73 mmol) and 10% palladium on carbon (104 mg, 0.097 mmol). Thereaction was stirred at RT. After 1 hour, the reaction mixture wasfiltered through Celite® brand filter aid, concentrated, diluted withDCM, and washed with water and brine. The residue was concentrated andused in the next reaction without further purification.

Thecis-4-(2-amino-5-morpholinophenylamino)-N-isopropylcyclohexanecarboxamide(315 mg, 0.874 mmol) was dissolved in EtOH (5 mL), and cyanogen bromide(139 mg, 1.311 mmol) was added. The reaction was stirred at RT. After 16hours, the reaction was diluted with DCM (50 mL) and washed with 1 Naqueous NaOH. The organic layer was concentrated to providecis-4-(2-amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamideas a light purple solid (210 mg, 62.3% yield). MS, m/z (C₂₁H₃₁N₅O₂):calcd, 385.2. found, 385.8 [M+H].

Step D:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution of TEA (0.091 mL, 0.654 mmol) and1H-benzo[d][1,2,3]triazol-1-ol hydrate (100 mg, 0.654 mmol) in DCM (2mL) was added 4-fluorobenzoyl chloride (0.064 mL, 0.545 mmol) dropwise,and the reaction was stirred at RT for 30 minutes. After 30 minutes, thesuspension was added to a solution ofcis-4-(2-amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide(210 mg, 0.545 mmol) in DCM (5 mL). The reaction was stirred at RT.After 3 days, the reaction mixture was concentrated, adsorbed onto aplug of silica gel, and purified by column chromatography, eluting with0-10% MeOH in DCM, to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a grey powder (95 mg, 34.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.57 (s, 1H), 8.29 (dd, J=6.1, 8.8 Hz, 2H), 7.73 (d, J=7.5 Hz, 1H),7.44 (s, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz, 2H),6.87, (d, J=8.8 Hz, 1H), 4.94 (brs, 1H), 3.90-3.99 (m, 1H), 3.78 (t,J=4.7 Hz, 4H), 3.18 (t, J=4.8 Hz, 4H), 2.74-2.84 (m, 2H), 2.55 (brs,1H), 2.03-2.11 (m, 2H), 1.67-1.78 (m, 2H), 1.54-1.63 (m, 2H), 1.10 (d,J=6.5 Hz, 6H). MS, m/z (C₂₈H₃₄FN₅O₃): calcd, 507.3. found, 507.9 [M+H].

Example 219

(E)-N-(6-Chloro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideStep A:cis-4-(2-Amino-6-chloro-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(2.27 g, 6.68 mmol) in EtOH (66.8 mL) was added tin(II) chloridedihydrate (6.03 g, 26.7 mmol). The reaction was stirred at 80° C. for 90minutes. The reaction mixture was concentrated, and the residue waspartitioned between EtOAc and 1 N aqueous NaOH. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and concentrated. Thecis-4-(2-amino-5-chlorophenylamino)-N-isopropylcyclohexanecarboxamideintermediate (2.07 g, 6.68 mmol) was dissolved in EtOH (20 mL), andcyanogen bromide (1.061 g, 10.02 mmol) was added. The reaction wasstirred at RT for 1 hour The reaction was diluted with 200 mL DCM andwashed with 1 N aqueous NaOH. The organic layer was concentrated toprovidecis-4-(2-amino-6-chloro-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide(2.77 g, 124% yield) as a brown oil. MS, m/z (C₁₇H₂₃ClN₄O): calcd,334.2. found, 334.8 [M+H].

Step B:(E)-N-(6-Chloro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-(2-amino-6-chloro-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamideand 4-fluorobenzoyl chloride using a method analogous to that used inthe preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(0.87 g, 28% yield). MS, m/z (C₂₄H₂₆ClFN₄O₂): calcd, 456.2. found, 456.9[M+H].

Example 220

(E)-4-Fluoro-N-(6-fluoro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A:cis-4-(5-Fluoro-2-nitrophenylamino)-N-isopropylcyclohexane-carboxamide

To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamidehydrochloride (0.1 g, 0.453 mmol) and DIPEA (0.237 mL, 1.359 mmol) inACN (3 mL) was added 2,4-difluoro-1-nitrobenzene (0.072 g, 0.453 mmol).The reaction was stirred overnight at 80° C. The reaction mixture wasconcentrated, adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 0-100% EtOAc in DCM, to providecis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide asa yellow powder (0.123 g, 84% yield).

Step B:(E)-4-Fluoro-N-(6-fluoro-1-(cis-4-(isopropylcarbamoyl)-cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution ofcis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(123 mg, 0.380 mmol) in EtOH (5 mL) was added ammonium formate (240 mg,3.80 mmol) and 10% palladium on carbon (40.5 mg, 0.038 mmol). Thereaction was stirred at RT for 1 hour. The reaction mixture was filteredthrough Celite® brand filter aid (washed with MeOH), concentrated, andredissolved in DCM (10 mL). The solution was washed with water, driedover anhydrous magnesium sulfate, filtered, and concentrated to affordcis-4-(2-amino-5-fluorophenylamino)-N-isopropylcyclohexanecarboxamide asa purple oil that crystallized upon standing. The diamine was dissolvedin THF (5 mL), cooled to 0° C., and 4-fluorobenzoyl isothiocyanate (97mg, 0.534 mmol) was added. The reaction was stirred at 0° C. for 15minutes, and then DIPEA (0.100 mL, 0.573 mmol) and EDC (110 mg, 0.573mmol) were added, and the reaction was stirred for 1 hour at 60° C. Thereaction mixture was concentrated, adsorbed onto a plug of silica gel,and purified by column chromatography, eluting with 0-100% EtOAc in DCM,to provide(E)-4-fluoro-N-(6-fluoro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas an off-white powder (137 mg, 81% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.09 (d, J=6.7 Hz, 6H), 1.55-1.80 (m, 4H), 2.04-2.12 (m, 2H), 2.53(br. s., 1H), 2.68-2.82 (m, 2H), 3.94-4.08 (m, 1H), 4.86 (br. s., 1H),7.02-7.12 (m, 1H), 7.25 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.53 (dd, J=8.8, 4.9Hz, 1H), 7.60 (dd, J=9.5, 1.9 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 8.32 (dd,J=8.8, 5.9 Hz, 2H), 12.82 (s, 1H). MS, m/z (C₂₄H₂₆F₂N₄O₂): calcd, 440.2.found, 440.7 [M+H].

Example 221

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)-cyclohexanecarboxamide

To a suspension of sodium hydride (70.6 mg, 2.94 mmol) and1H-1,2,4-triazole (203 mg, 2.94 mmol) in NMP (1 mL) was addedcis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(100 mg, 0.294 mmol). The resulting suspension was irradiated in amicrowave reactor for 1 hour at 150° C. The reaction mixture waspartitioned between water and EtOAc. The aqueous layer was extractedwith EtOAc (×2). The combined organic layers were then washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide a yellow oil that crystallized upon standing toprovidecis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)cyclohexanecarboxamideas a yellow solid (100 mg, 91% yield).

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a solution ofcis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)-cyclohexanecarboxamide(100 mg, 0.269 mmol) in EtOH (3 mL) was added tin(II) chloride dihydrate(242 mg, 1.074 mmol). The reaction was stirred at 80° C. After 3 hours,another four equivalents of tin(II) chloride dihydrate (242 mg, 1.074mmol) was added, and the reaction was stirred at 80° C. for anadditional 3 hours, and then at RT overnight. The reaction mixture wasconcentrated, and the residue was partitioned between EtOAc and 1 Naqueous sodium hydroxide. The aqueous layer was extracted with EtOAc;the combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated. The diamine was dissolved in THF (3 mL),cooled to 0° C., and 4-fluorobenzoyl isothiocyanate (53.5 mg, 0.296mmol) was added. The reaction was stirred at 0° C. for 30 minutes, thenDIPEA (0.070 mL, 0.403 mmol) and EDC (77 mg, 0.403 mmol) were added, andthe reaction was stirred for 1 hour at 60° C. The residual material wasconcentrated, adsorbed onto a plug of silica gel, and purified by columnchromatography, eluting with 20-100% EtOAc in DCM, to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas an off-white powder (44 mg, 33.5% yield). MS, m/z (C₂₆H₂₈FN₇O₂):Calc'd, 489.2. found, 489.9 [M+H].

Example 222

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexane-carboxamide

A suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(100 mg, 0.293 mmol) and morpholine (0.256 mL, 2.93 mmol) in 2-propanol(1 mL) was irradiated in the microwave for 1 hour at 150° C. Thereaction mixture was concentrated, adsorbed onto a plug of silica gel,and purified by column chromatography, eluting with 0-100% EtOAc in DCM,to providecis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamideas a yellow powder (121 mg, quantitative yield). MS, m/z (C₁₉H₂₉N₅O₄):Calcd, 508.3. found, 509.1 [M+H].

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

To a solution ofcis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamide(121 mg, 0.309 mmol) in EtOH (5 mL) and EtOAc (3 mL) was added 10%palladium on carbon (32.9 mg, 0.031 mmol). The reaction was stirredunder a hydrogen atmosphere (H₂ balloon) at RT. After 3 hours, thereaction mixture was filtered through Celite® brand filter aid (washedwith MeOH and DCM), and concentrated to affordcis-4-(5-amino-2-morpholinopyridin-4-ylamino)-N-isopropylcyclohexane-carboxamideas a dark oil. The diamine was dissolved in THF (3 mL), and4-fluorobenzoyl isothiocyanate (61.8 mg, 0.341 mmol) was added. Thereaction was stirred at 0° C. for 15 minutes, and then EDC (89 mg, 0.465mmol) and DIPEA (0.081 mL, 0.465 mmol) were added. The reaction wasstirred at 60° C. for 2 hours and then overnight at RT. After 16 hours,the reaction mixture was concentrated, and adsorbed onto a plug ofsilica gel. The residue was purified by column chromatography, elutingwith 0-100% EtOAc in DCM, to provide(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas a light-yellow powder (38 mg, 24.11% yield). MS, m/z (C₂₇H₃₃FN₆O₃):calcd, 508.3. found, 509.1 [M+H].

Example 223

N-((2E)-6-(1,1-Dioxido-4-thiomorpholinyl)-1-(cis-4-((1-methylethyl)carbamoyl)cyclohexyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ylidene)-4-fluorobenzamideStep A:cis-N-Isopropyl-4-(5-nitro-2-(1,1-dioxido-4-thiomorpholinyl)pyridin-4-ylamino)cyclohexanecarboxamide

A suspension ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(100 mg, 0.293 mmol) and thiomorpholine-1,1-dioxide (198 mg, 1.467 mmol)in 2-propanol (1 mL) was irradiated in the microwave for 90 minutes at170° C. The reaction mixture was concentrated, adsorbed onto a plug ofsilica gel, and purified by column chromatography, eluting with 0-100%EtOAc in DCM, to providecis-N-isopropyl-4-(5-nitro-2-(1,1-dioxido-4-thiomorpholinyl)pyridin-4-ylamino)cyclohexanecarboxamideas a yellow powder (112 mg, 87% yield). MS, m/z (C₁₉H₂₉N₅O₅S): Calcd,439.2. found, 440.1 [M+H].

Step B:N-((2E)-6-(1,1-Dioxido-4-thiomorpholinyl)-1-(cis-4-((1-methylethyl)carbamoyl)cyclohexyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ylidene)-4-fluorobenzamide

The title compound was prepared in 2 steps fromcis-N-isopropyl-4-(5-nitro-2-(1,1-dioxido-4-thiomorpholinyl)pyridin-4-ylamino)cyclohexanecarboxamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas a light-yellow powder (24 mg, 17% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.08 (d, J=6.6 Hz, 6H), 1.52-1.81 (m, 4H), 1.93-2.12 (m, 2H), 2.54(br. s., 1H), 2.73-2.90 (m, 2H), 3.12 (br. s., 4H), 3.92-4.07 (m, 1H),4.14 (br. s., 4H), 4.87 (br. s., 1H), 7.20-7.32 (m, 2H), 7.50 (s, 1H),7.78 (d, J=7.6 Hz, 1H), 7.89-7.99 (m, 1H), 8.30 (br. s., 2H), 12.61 (br.s., 1H). MS, m/z (C₂₇H₃₃FN₆O₄S): calcd, 556.2. found, 557.1 [M+H].

Example 224

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-(methylsulfonyl)-piperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-(4-(methylsulfonyl)piperazin-1-yl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

The title compound was prepared using a method analogous to thepreparation ofcis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexane-carboxamideas a yellow powder (133 mg, 97% yield). MS, m/z (C₂₀H₃₂N₆O₅S): calcd,468.2. found, 468.9 [M+H].

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps fromcis-N-isopropyl-4-(2-(4-(methylsulfonyl)piperazin-1-yl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(125 mg, 76% yield). MS, m/z (C₂₈H₃₆FN₇O₄S): calcd, 585.2. found, 585.9[M+H].

Example 225

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-N-Isopropyl-4-(2-(4-methylpiperazin-1-yl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

The title compound was prepared using a method analogous to thepreparation ofcis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexane-carboxamideto providecis-N-isopropyl-4-(2-(4-methylpiperazin-1-yl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideas a yellow powder (123 mg, quantitative yield). MS, m/z (C₂₀H₃₂N₆O₃):calcd, 404.2. found, 405.0 [M+H].

Step B:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps fromcis-N-isopropyl-4-(2-(4-methylpiperazin-1-y1)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(139 mg, 88% yield). MS, m/z (C₂₈H₃₆FN₇O₂): calcd, 521.3. found, 522.0[M+H].

Example 226

(E)-4-Fluoro-N-(6-(2-hydroxy-2-methylpropylamino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A:cis-4-(2-(2-Hydroxy-2-methylpropylamino)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

The title compound was prepared using a method analogous to thepreparation ofcis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexane-carboxamide.The product was obtained as a yellow powder (90 mg, 78% yield). MS, m/z(C₁₉H₃₁N₅O₄): calcd, 393.2. found, 394.2 [M+H].

Step B:(E)-4-Fluoro-N-(6-(2-hydroxy-2-methylpropylamino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps from(cis-4-(2-(2-hydroxy-2-methylpropylamino)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(32 mg, 27.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J=6.6 Hz,6H), 1.17 (s, 6H), 1.55-1.77 (m, 4H), 2.03-2.11 (m, 2H), 2.53-2.56 (m,1H), 2.70-2.81 (m, 2H), 3.19 (d, J=6.0 Hz, 2H), 3.92-4.08 (m, 1H), 4.65(s, 1H), 4.74 (br. s., 1H), 5.80 (t, J=5.8 Hz, 1H), 6.80 (s, 1H), 7.24(dd, J=8.9 Hz, 8.9 Hz, 2H), 7.71 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 8.29(dd, J=8.9, 5.9 Hz, 2H), 12.48 (s, 1H). MS, m/z (C₂₇H₃₅FN₆O₃): calcd,510.3. found, 511.2 [M+H].

Example 227

(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: N-(cis-4-Aminocyclohexyl)isobutyramide hydrochloride

To a solution of tert-butyl cis-4-aminocyclohexylcarbamate (500 mg,2.333 mmol) in DCM (20 mL) was added isobutyric anhydride (0.407 mL,2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction wasstirred at RT overnight. The resulting white precipitate was collectedby vacuum filtration and dried in vacuo to generateN-(cis-4-aminocyclohexyl)isobutyramide hydrochloride as an off-whitepowder (508 mg, 99% yield).

Step B:N-(cis-4-(5-(Hydroxymethyl)-2-nitrophenylamino)cyclohexyl)-isobutyramide

To a suspension of N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride(200 mg, 0.906 mmol) and DIPEA (0.432 mL, 2.471 mmol) in ACN (2 mL) wasadded (3-fluoro-4-nitrophenyl)methanol (141 mg, 0.824 mmol). Thereaction was stirred overnight at 80° C. After 16 hours, the reactionmixture was concentrated and the residue purified by columnchromatography, eluting with 0-100% EtOAc in DCM, to provideN-(cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)isobutyramideas an orange foam (176 mg, 63.7% yield). MS, m/z (C₁₇H₂₅N₃O₄): calcd,335.2. found, 336.0 [M+H].

Step C:(E)-4-Fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The desired compound was prepared in 2 steps fromN-(cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)isobutyramideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(75 mg, 63.3% yield). MS, m/z (C₂₅H₂₉FN₄O₃): calcd, 452.2. found, 453.0[M+H].

Step D:(E)-4-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(75 mg, 0.166 mmol) in DCM (5 mL) was added thionyl chloride (0.060 mL,0.829 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed, and the residue wassuspended in ACN (5 mL) and re-concentrated to remove residual thionylchloride. The residue was resuspended in ACN (3 mL), cooled to 0° C.,and 2-(piperidin-4-yl)propan-2-ol (95 mg, 0.663 mmol) was added. Thereaction was stirred overnight at RT. After 16 hours, the reactionmixture was concentrated and partitioned between EtOAc and water. Theorganic layer was concentrated and the residue was purified by columnchromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH₄OH) in DCM toprovide(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (30 mg, 31.3% yield). MS, m/z (C₃₃H₄₄FN₅O₃): calcd,577.3. found, 578.1 [M+H].

Example 228

(E)-3-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideand 2-(piperidin-4-yl)propan-2-ol using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(58 mg, 46.4% yield). MS, m/z (C₃₃H₄₄FN₅O₃): calcd, 577.3. found, 578.1[M+H].

Example 229

(E)-N-(1-(trans-4-Acetamidocyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideStep A: N-(trans-4-Aminocyclohexyl)acetamide hydrochloride

To a solution of tert-butyl trans-4-aminocyclohexylcarbamate (500 mg,2.333 mmol) in DCM (20 mL) was added acetic anhydride (0.231 mL, 2.450mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HClin dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirredat RT for 3 days. The resulting white solid was collected by vacuumfiltration and dried in vacuo to generateN-(trans-4-aminocyclohexyl)acetamide hydrochloride as a white powder(0.49 g, 109% yield).

Step B:N-(trans-4-(5-(Hydroxymethyl)-2-nitrophenylamino)cyclohexyl)-acetamide

To a suspension of N-(trans-4-aminocyclohexyl)acetamide hydrochloride(200 mg, 1.038 mmol) and DIPEA (0.494 mL, 2.83 mmol) in ACN (2 mL) wasadded (3-fluoro-4-nitrophenyl)methanol (161 mg, 0.944 mmol). Theresulting mixture was stirred overnight at 80° C. After 16 hours, thereaction was concentrated and the residue purified by columnchromatography, eluting with 0-10% MeOH in DCM, to provideN-(trans-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)acetamide asa yellow powder (50 mg, 17.24% yield). MS, m/z (C₁₅H₂₁N₃O₄): calcd,307.2. found, 308.1 [M+H].

Step C:(E)-N-(1-(trans-4-Acetamidocyclohexyl)-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared in 2 steps fromN-(trans-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)-acetamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(41 mg, 53.6% yield). MS, m/z (C₂₃H₂₅FN₄O₃): calcd, 424.2. found, 425.1[M+H].

Step D:(E)-N-(1-(trans-4-Acetamidocyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared from(E)-N-(1-(trans-4-acetamidocyclohexyl)-6-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideand 2-(piperidin-4-yl)propan-2-ol using a method analogous to that usedin the preparation of(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(11 mg, 20.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (s, 6H),1.13-1.30 (m, 5H), 1.40-1.54 (m, 2H), 1.60-1.68 (m, 2H), 1.76-1.91 (m,7H), 1.97-2.06 (m, 2H), 2.85-2.94 (m, 2H), 3.53 (s, 2H), 3.82 (br. s.,1H), 3.99 (s, 1H), 4.83 (br. s., 1H), 7.16 (d, J=7.3 Hz, 1H), 7.28 (dd,J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.81 (d,J=7.3 Hz, 1H), 8.20-8.29 (m, 2H), 12.76 (br. s., 1H). MS, m/z(C₃₁H₄₀FN₅O₃): calcd, 549.3. found, 550.2 [M+H].

Example 230

(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: tert-Butyl3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

To a solution of 7-tert-butyl 3-ethyl5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-3,7(8H)-dicarboxylate (0.9 g,3.04 mmol) in THF (20 mL) at 0° C., was added 3 M methylmagnesium iodidein diethyl ether (3.04 mL, 9.11 mmol) dropwise. The reaction was stirredovernight at RT. After 16 hours, the reaction was quenched withsaturated aqueous ammonium chloride and extracted with EtOAc. Theorganic layer was concentrated to provide tert-butyl3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylateas a white powder (0.4 g, 46.6% yield).

Step B:2-(5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-oldihydrochloride

To a solution of tert-butyl3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate(0.40 g, 1.417 mmol) in DCM (10 mL) at 0° C., was added 2 M HCl indiethyl ether (3.54 mL, 7.08 mmol) dropwise. The reaction was stirredovernight at RT. After 16 hours, the white precipitate was collected byvacuum filtration, washed with ether, and dried in vacuo. The residuewas resuspended in 1,4-dioxane (10 mL) and 4 M HCl in dioxane (1.78 mL,7.08 mmol) was added. The mixture was heated to 60° C. and stirredvigorously overnight. After 16 hours, the suspension was concentrated toa white powder and dried in vacuo to generate2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-oldihydrochloride (0.373 g, 103% yield).

Step C:(E)-4-Fluoro-N-(6-((3-(2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

To a 0° C. cooled solution of(E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide(100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL,1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30minutes. After 30 minutes, the solvent was removed at reduced pressure,and the residue was suspended in ACN (2 mL) and re-concentrated toremove residual thionyl chloride. The residue was added to a suspensionof the2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-oldihydrochloride (169 mg, 0.663 mmol) and potassium carbonate (244 mg,1.768 mmol) in 4 mL DMF. The reaction was stirred overnight at RT. After16 hours, the reaction mixture was partitioned between water and EtOAc.The aqueous layer was extracted with EtOAc. The combined organic layerswere washed with water and brine, and concentrated to a brown oil. Theresidue was purified by HPLC (0.1% NH₄OH in ACN/water) to generate(E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-O-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideas a white powder (13 mg, 9.54% yield). MS, m/z (C₃₃H₄₁FN₈O₃): calcd,616.3. found, 617.4 [M+H].

Example 231

(E)-N-(1-(cis-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamideStep A: 2-(1-(3-Fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol

To a solution of 3-fluoro-4-nitrobenzaldehyde (0.5 g, 2.96 mmol) and2-(piperidin-4-yl)propan-2-ol (0.466 g, 3.25 mmol) in DCM (25 mL) wasadded AcOH (0.017 mL, 0.296 mmol) and sodium triacetoxyborohydride(0.689 g, 3.25 mmol), and the reaction was stirred at RT for 1 hour.After 1 hour, the reaction was quenched by the addition of 1 N aqueousNaOH (15 mL), and the layers were separated. The aqueous layer wasextracted with DCM, and the combined organic layers were washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residual product was adsorbed onto a plug of silicagel, and purified by column chromatography, eluting with 0-100% EtOAc inDCM, to provide 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-olas a yellow oil (0.75 g, 86% yield).

Step B:cis-4-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid

To a suspension of cis-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265mmol). The reaction was stirred at 75° C. After 48 hours, the reactionmixture was concentrated, diluted with water (10 mL), and extracted withDCM and EtOAc. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated to providecis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid as an orange powder (0.76 g, 143% yield).

Step C:cis-4-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamide

To a solution ofcis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid (0.53 g, 1.263 mmol) in DMF (7 mL) was added CDI (0.410 g, 2.53mmol) and aqueous ammonium hydroxide (100 μL, 2.53 mmol). The reactionwas stirred overnight at RT. After 16 hours, the reaction mixture waspartitioned between water and DCM and the aqueous layer was extractedwith DCM. The combined organic layers were washed with water and brine,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by column chromatography, eluting with 0-100%(90:9:1 DCM/MeOH/NH4OH)/DCM, to providecis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamideas an orange foam (0.213 g, 40.3% yield). MS, m/z (C₂₂H₃₄FN₄O₄): calcd,418.3. found, 419.1 [M+H].

Step D:(E)-N-(1-(cis-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide

To a solution ofcis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamide(213 mg, 0.509 mmol) in EtOH (5 mL) was added 10% palladium on carbon(54.2 mg, 0.051 mmol). A hydrogen balloon was placed on the vessel, andthe reaction was stirred vigorously under a hydrogen atmosphere at RT.After 2 hours, the reaction mixture was filtered through Celite® brandfilter aid (washed with 1:1 MeOH/DCM) to providecis-4-(2-amino-5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)phenylamino)cyclohexanecarboxamideas a dark oil.

The diamine was dissolved in THF (3 mL), cooled to 0° C., and3-fluorobenzoyl isothiocyanate (56.0 mg, 0.309 mmol) was added. Thereaction was stirred at 0° C. for 15 minutes, then EDC (74.0 mg, 0.386mmol) and DIPEA (0.067 mL, 0.386 mmol) were added, and the reaction wasstirred at 60° C. for 2 hours. The reaction mixture was concentrated andpartitioned between DCM and water. The organic layer was dried overanhydrous magnesium sulfate, filtered, concentrated, and the residue waspurified by column chromatography, eluting with 0-100% EtOAc in DCM, toprovide(E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamideas an off-white powder (75 mg, 54.4% yield). MS, m/z (C₃₀H₃₈FN₅O₃):calcd, 535.3. found, 536.1 [M+H].

Example 232

(E)-3-(N-Allylsulfamoyl)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamideStep A: 3-(N-Allylsulfamoyl)benzoyl isothiocyanate

To a suspension of 3-(N-allylsulfamoyl)benzoic acid (2 g, 8.29 mmol) in1,2-dichloroethane (25 mL) was added thionyl chloride (1.271 mL, 17.41mmol) dropwise. The suspension was stirred for 2 hours at 80° C. After 2hours, the reaction mixture was concentrated to an off-white solid. Thesolid was redissolved in 25 mL acetone, and potassium isothiocyanate(0.967 g, 9.95 mmol) was added. A precipitate formed immediately uponaddition. The reaction was stirred at 50° C. After 2 hours, the reactionwas filtered, concentrated, and adsorbed onto a silca-gel pre column.The residue was purified by column chromatography, eluting with 20-100%EtOAc in hexanes, to provide 3-(N-allylsulfamoyl)benzoyl isothiocyanateas an off-white solid (0.71 g, 30.3% yield). MS, m/z (C₁₁H₁₀N₂O₃S₂):calcd, 282.0. found, 282.9 [M+H].

Step B:(E)-3-(N-Allylsulfamoyl)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamideand 3-(N-allylsulfamoyl)benzoyl isothiocyanate using a method analogousto that used for the preparation of(E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide(75 mg, 46% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (br. s., 6H),1.24 (br. s., 3H), 1.56-1.78 (m, 6H), 1.85 (br. s., 2H), 2.13-2.27 (m,2H), 2.59 (br. s., 1H), 2.69-3.04 (m, 4H), 3.48 (br. s., 4H), 4.02 (br.s., 1H), 4.79 (br. s., 1H), 5.03 (d, J=11.1 Hz, 1H), 5.16 (d, J=17.5 Hz,1H), 5.62-5.78 (m, 1H), 6.87 (br. s., 1H), 7.20 (br. s., 1H), 7.39-7.64(m, 3H), 7.69-7.79 (m, 1H), 7.93 (d, J=7.3 Hz, 1H), 8.09 (br. s., 1H),8.45-8.68 (m, 2H), 12.81 (br. s., 1H). MS, m/z (C₃₃H₄₄N₆O₅S): calcd,636.3. found, 636.9 [M+H].

Example 233

(E)-N-(1-(trans-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideStep A:trans-4-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid

To a suspension of trans-4-aminocyclohexanecarboxylic acid (0.199 g,1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265mmol). The reaction was stirred at 75° C. After 48 hours, the reactionmixture was concentrated, diluted with water (10 mL) and extracted withDCM and EtOAc. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated to providetrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid (0.524 g, 1.249 mmol, 99% yield) as an orange powder.

Step B:trans-4-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamide

To a solution oftrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylicacid (0.53 g, 1.263 mmol) in DMF (5 mL) was added CDI (0.410 g, 2.53mmol). The reaction was stirred at RT for 1 hour, and then concentratedaqueous ammonium hydroxide (0.098 mL, 2.53 mmol) was added, and thereaction was stirred overnight. After 16 hours, the reaction mixture waspartitioned between water and EtOAc. The aqueous layer was extractedwith EtOAc, and the combined organic layers were washed with water andbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by column chromatography, elutingwith 50-100% (90:9:1 DCM/MeOH/NH₄OH)/DCM, to providetrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamideas an orange powder (0.39 g, 73.8% yield). MS, m/z (C₂₂H₃₄FN₄O₄): calcd,418.3. found, 419.1 [M+H].

Step C:(E)-N-(1-(trans-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared in 2 steps fromtrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamideusing a method analogous to that used in the preparation of(E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide(75 mg, 45% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (s, 6H),1.15-1.33 (m, 3H), 1.59-1.73 (m, 5H), 1.80-1.93 (m, 4H), 1.96-2.04 (m,2H), 2.30-2.47 (m, 3H), 2.91 (br. s., 2H), 3.53 (br. s., 2H), 4.78 (br.s., 1H), 6.77 (br. s., 1H), 7.14-7.21 (m, 1H), 7.25-7.34 (m, 3H),7.46-7.59 (m, 2H), 8.27 (dd, J=8.5, 5.9 Hz, 2H), 12.77 (br. s., 1H). MS,m/z (C₃₀H₃₈FN₅O₃): calcd, 535.3. found, 536.1 [M+H].

Example 234

(E)-N-(1-(trans-4-Carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide

The title compound was prepared in 2 steps fromtrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamideusing a method analogous to the preparation of(E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide(75 mg, 45%). MS, m/z (C₃₀H₃₈FN₅O₃): calcd, 535.3. found, 536.1 [M+H].

Example 235

(E)-3-(N-Allylsulfamoyl)-N-(1-(trans-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared in 2 steps fromtrans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamideusing a method analogous to the preparation of(E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide(69 mg, 35% yield). MS, m/z (C₃₀H₃₈FN₅O₃): calcd, 636.3. found, 636.9[M+H].

Example 236

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

Step A:cis-N-Isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

To a solution ofcis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(0.100 g, 0.293 mmol) in DMF (0.6 mL) was added sodium methanesulfinate(0.042 g, 0.352 mmol), and the reaction mixture was heated at 100° C.for 2 hours. The reaction was conducted twice and the mixtures werecombined and concentrated under reduced pressure and the yellow residuepurified by flash chromatography, eluting with 0-80% 9:1 DCM/MeOH:DCM toaffordcis-N-isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamideas a yellow solid. MS (ESI pos. ion) m/z: 385.0 [M+H].

Step B:cis-4-(5-Amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-N-isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide(0.177 g, 0.460 mmol) in MeOH (2 mL) was added anhydrous tin (II)chloride (0.349 g, 1.842 mmol). The reaction mixture was heated at 80°C. for 3 hours and was concentrated under vacuum. The remaining residuewas dissolved in EtOAc and washed with 1N aqueous NaOH followed bybrine. The organic layer was dried over sodium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography, elutingwith 0-100% 90/10/1 DCM/MeOH/NH₄OH: DCM to affordcis-4-(5-amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(0.150 g, 92% yield). MS (ESI pos. ion) m/z: 355.2 [M+H].

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

A solution ofcis-4-(5-Amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide(0.069 g, 0.195 mmol) in THF (0.5 mL) was cooled to 0° C. and4-fluorobenzoyl isothiocyanate (0.053 g, 0.292 mmol) was added as a THFsolution. The mixture was stirred at 0° C. for 30 minutes and then waswarmed to 20° C. and stirred for 1 hour. To the mixture was added DIPEA(0.051 mL, 0.292 mmol) and EDC (0.056 g, 0.292 mmol), and the reactionwas heated at 60° C. for 1 hour. The reaction mixture was diluted withDCM and then washed with water and brine. The organic layer wasconcentrated under vacuum. The sample was purified by flashchromatography, eluting with 0-70% 90/10/1 DCM/MeOH/NH₄OH: DCM to affordimpure product as a light yellow solid. The impure material was furtherpurified by preparative TLC, eluting with 90/10/1 DCM/MeOH/NH₄OH: DCM toafford(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideas a pale yellow solid (0.046 g, 47.1% yield). MS, m/z (C₂₄H₂₈FN₅O₄S);Calcd, 501.58. found 502.2 [M+H].

Example 237

Methyl1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-ylcarbamate

Step A: 1-(3-Fluoro-4-nitrobenzyl)piperidine

To a mixture of 3-fluoro-4-nitrobenzaldehyde (4.85 g, 28.7 mmol),piperidine (3.12 mL, 31.5 mmol) and 20 drops of AcOH in DCM was addedsodium triacetoxyborohydride (6.69 g, 31.5 mmol), and the resultingsuspension was stirred at RT for 30 minutes. The reaction was made basicwith 2N aqueous NaOH, and extracted with DCM. The organic layer waswashed with brine and was dried over sodium sulfate, filtered andconcentrated in vacuo to yield a red oil. The residual oil was purifiedvia MPLC, eluting with a gradient of 0-100% EtOAc in hexane to yield1-(3-fluoro-4-nitrobenzyl)piperidine (3.98 g, 16.70 mmol, 58.2% yield)as an orange oil.

Step B:cis-N-Isopropyl-4-(2-nitro-5-(piperidin-1-ylmethyl)phenylamino)cyclohexanecarboxamide

cis-4-Amino-N-isopropylcyclohexanecarboxamide hydrochloride (1.734 g,7.86 mmol) was suspended in ACN (4.09 mL, 6.55 mmol), and DIPEA (1.144mL, 6.55 mmol) was added. After stirring for 10 minutes at RT, thesolution was added to a solution of 1-(3-fluoro-4-nitrobenzyl)piperidine(1.56 g, 6.55 mmol) in ACN (8.73 mL) and DIPEA (2.287 mL, 13.10 mmol).The reaction was heated at reflux for three days. The reaction wasdiluted with water and DCM, and the layers were separated. The organiclayer was dried over Na₂SO₄, filtered and concentrated to yield theproduct as a dark red solid. The residue was purified via HPLC (elutingwith 100% 90:10:1 DCM:MeOH:NH₄OH to yieldcis-N-isopropyl-4-(2-nitro-5-(piperidin-1-ylmethyl)phenylamino)cyclohexanecarboxamideas an orange-red solid.

Step C:4-(2-Amino-5-(piperidin-1-ylmethyl)phenylamino)-N-isopropylcyclohexanecarboxamide

To a round bottom flask was addedcis-N-isopropyl-4-(2-nitro-5-(piperidin-1-ylmethyl)phenylamino)cyclohexanecarboxamide(1.400 g, 3.48 mmol) under nitrogen. Palladium on carbon (0.370 g, 0.348mmol) was added, followed by EtOH (28.3 mL) via syringe. To the reactionwas added ammonium formate (2.193 g, 34.8 mmol), and the reactionmixture was stirred at RT overnight. The reaction mixture was filteredthrough Celite® brand filter aid, concentrated and diluted with 90:10:1DCM:MeOH:NH₄OH and water. The layers were separated, and the aqueouslayer was washed once more. The organics were dried over sodium sulfate,filtered and concentrated to yieldcis-4-(2-amino-5-(piperidin-1-ylmethyl)phenylamino)-N-isopropylcyclohexanecarboxamide(1.18 g, 3.17 mmol, 91% yield) as a dark red solid.

Step D: Methyl1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-ylcarbamate

To a solution ofcis-4-(2-amino-5-(piperidin-1-ylmethyl)phenylamino)-N-isopropylcyclohexanecarboxamide(0.300 g, 0.805 mmol) in MeOH (4.5 mL) was added1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.166 g, 0.805 mmol)and p-toluenesulfonic acid monohydrate (0.168 g, 0.886 mmol). Thereaction mixture was heated at 80° C. for 2 hours and then concentratedunder vacuum. The residue was dissolved in DCM and was washed withsaturated aqueous NaHCO₃. The organic layer was dried over sodiumsulfate and concentrated under vacuum. The residue was purified by flashchromatography, eluting with 0-100% 90:10:1 DCM/MeOH/NH₄OH: DCM toafford methyl1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-ylcarbamate(0.239 g, 65.1% yield). MS, m/z (C₂₅H₃₇N₅O₃); calcd, 455.59. found 456.2[M+H]. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.23 (d, J=6.55 Hz, 6H) 1.38-1.49(m, 2H) 1.52-1.67 (m, 4H) 1.67-1.85 (m, 6H) 2.10-2.20 (m, 2H) 2.34-2.51(m, 4H) 2.58-2.73 (m, 2H) 3.54-3.66 (m, 1H) 3.79 (s, 3H) 4.20 (dt,J=13.70, 6.70 Hz, 1H) 4.86 (tt, J=12.79, 4.47 Hz, 1H) 5.34 (br. d,J=7.20 Hz, 1H) 7.13-7.25 (m, 2H) 7.61 (br. s., 1H) 11.29 (br. s., 1H).

Example 238

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

Step A:cis-N-Isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide

To a solution ofcis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(0.100 g, 0.309 mmol) in DMF (0.55 mL) was added sodium methanesulfinate(0.045 g, 0.371 mmol), and the reaction mixture was heated at 100° C.for 2 hours. The mixture was concentrated under vacuum, and the residuewas purified by flash chromatography, eluting with 0-70% 9:1 DCM/MeOH tocis-N-isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamideas a bright orange solid (0.124 g, 105% yield). MS (ESI pos. ion) m/z:384.0 [M+H].

Step B:cis-4-(2-Amino-5-(methylsulfonyl)phenylamino)-N-isopropylcyclohexanecarboxamide

To a solution ofcis-N-Isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide(0.120 g, 0.313 mmol) in MeOH (1.2 mL) was added 5% Pd/C (0.067 g, 0.031mmol) and ammonium formate (0.154 mL, 3.13 mmol) (exotherm). Thereaction mixture was stirred at 20° C. for 1 hour and then the mixturewas filtered through a pad of Celite® brand filter aid, washing withMeOH. The filtrate was concentrated under vacuum, and the remainingresidue was dissolved in DCM then washed with water. The organic layerwas concentrated under vacuum. The residue was purified by flashchromatography, eluting with 0-80% 90:10:1 DCM/MeOH/NH₄OH: DCM to affordcis-4-(2-amino-5-(methylsulfonyl)phenylamino)-N-isopropylcyclohexanecarboxamideas a pale yellow oil (0.107 g, 97% yield). MS (ESI pos. ion) m/z: 354.2[M+H].

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared fromcis-4-(2-amino-5-(methylsulfonyl)phenylamino)-N-isopropylcyclohexanecarboxamideusing a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide,as an off-white solid (0.111 g, 75% yield). MS, m/z (C₂₅H₂₉FN₄O₄S):calcd, 500.59. found 501.2 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) d ppm 1.09(d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.14 (m, J=13.10 Hz, 2H) 2.51-2.57(m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 3.99-4.10 (m, 1H) 4.72-4.88 (m,1H) 7.22-7.29 (m, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79 (m, 2H)8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.09-2.19 (m,2H) 2.51-2.57 (m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 4.05 (sxt, J=6.94Hz, 1H) 4.72-4.88 (m, 1H) 7.25 (s, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79(m, 2H) 8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H).

Example 239

(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(thiomorpholine1,1-dioxide)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

Step A: cis-N-Isopropyl-4-(5-(thiomorpholine1,1-dioxide)-2-nitrophenylamino)cyclohexanecarboxamide

To a solution ofcis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide(0.100 g, 0.309 mmol) in NMP (0.5 mL) was added thiomorpholine1,1-dioxide (0.209 g, 1.546 mmol), and the reaction mixture wasirradiated at 200° C. in a microwave reactor for 2.5 hours. The mixturewas diluted with EtOAc and washed with water, brine, and the organiclayer concentrated under vacuum. The sample was purified by flashchromatography, eluting with 0-70% 90:10:1 DCM/MeOH/NH₄OH: DCM to affordcis-N-isopropyl-4-(5-(thiomorpholine1,1-dioxide)-2-nitrophenylamino)cyclohexanecarboxamide as an orange oil(0.044 g, 32.4% yield). MS (ESI pos. ion) m/z: 439.2 [M+H].

Step B: cis-4-(2-Amino-5-(thiomorpholine1,1-dioxide)phenylamino)-N-isopropylcyclohexanecarboxamide

The title compound was prepared fromcis-N-isopropyl-4-(5-(thiomorpholine1,1-dioxide)-2-nitrophenylamino)cyclohexanecarboxamide using a methodanalogous to the preparation ofcis-4-(2-amino-5-(methylsulfonyl)phenylamino)-N-isopropylcyclohexanecarboxamide,as a purple oil (25 mg). MS (ESI pos. ion) m/z: 409.2 [M+1-1].

Step C:(E)-4-Fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(thiomorpholine1,1-dioxide)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide

The title compound was prepared from cis-4-(2-amino-5-(thiomorpholine1,1-dioxide)phenylamino)-N-isopropylcyclohexanecarboxamide (0.025 g,0.061 mmol) using a method analogous to that used in the preparation of(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide,as a light yellow solid. MS m/z (C₂₈H₃₄FN₅O₄S), calcd 555.67. found556.2 [M+H].

Example 240

(E)-N-(1-(trans-3-Cyano-3-(pyridin-2-yl)cyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

Step A: 3-Cyano-3-(pyridin-2-yl)cyclobutyl methanesulfonate

To a solution of 3-hydroxy-1-(pyridin-2-yl)cyclobutanecarbonitrile (WO2007/060484)(10.996 g, 63.1 mmol) in dry DCM (100 mL) and pyridine(20.59 mL, 252 mmol), was added (with stirring and cooling in an icewater bath) methane sulfonyl chloride (4.88 mL, 63.1 mmol). The mixturewas stirred at RT for 25 hours. The solvent was removed at reducedpressure, and the residue was partitioned between EtOAc and aqueousNaHCO₃. The organic phase was washed with aqueous NaHCO₃ and wasconcentrated at reduced pressure. The residue was eluted through a shortpad of silica gel (eluent 30%-50% EtOAc/hexane). The solvent wasremoved, and the resulting oil was crystallized from toluene on dilutionwith hexane to afford the title compound as a 3:1 mixture of geometricalisomers (assessed by NMR).

Step B: 3-Azido-1-(pyridin-2-yl)cyclobutanecarbonitrile

To a solution of 3-cyano-3-(pyridin-2-yl)cyclobutyl methanesulfonate(4.008 g, 15.89 mmol) in dry DMF (20 mL) was added sodium azide (2.066g, 31.8 mmol), and the mixture was stirred in an oil bath at 90° C. for48 hours under a N₂ atmosphere. The reaction was diluted with EtOAc andwater, and the layers were separated. The organic layer was washed withwater and concentrated under vacuum. The residue was chromatographed onsilica gel, eluting with 40% EtOAc/hexane to afford the title compound,a 3:1 mixture of geometrical isomers, as a colourless oil m/z 200 MH+.

Step C: 3-Amino-1-(pyridin-2-yl)cyclobutanecarbonitrile

To a solution of 3-azido-1-(pyridin-2-yl)cyclobutanecarbonitrile (3.375g, 16.94 mmol) in THF (30 mL) and water (8 mL) was addedtriphenylphosphine (5.33 g, 20.33 mmol) with cooling and stirring in anice-water bath. The mixture was stirred at RT overnight. The reactionwas diluted with 1N aqueous HCl and EtOAc. The acidic aqueous layer wasseparated and retained. The organic layer was washed with water, andthen the combined aqueous layers were washed with EtOAc and basified byaddition of 6 N aq NaOH. The product amine was extracted with EtOAc. Theorganic phase was concentrated to afford the title compound as acolorless oil and a 3:1 mixture of geometrical isomers, which was driedunder vacuum and used without further purification.

Step D:cis-3-(2-Chloro-5-nitropyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrileandtrans-3-(2-chloro-5-nitropyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile

To a suspension of 2,4-dichloro-5-nitropyridine (2.39 g, 12.38 mmol) inACN (20 mL) was added DIPEA (4.33 mL, 24.77 mmol) and3-amino-1-(pyridin-2-yl)cyclobutanecarbonitrile (2.252 g, 13.00 mmol).The reaction mixture was heated at 80° C. for 8 hours. The reactionmixture was concentrated under vacuum, and the remaining residue wasdissolved in DCM then washed with water and brine. The organic layer wasconcentrated under vacuum. The residue was purified by flashchromatography, eluting with 0-70% EtOAc/hexane to afford a mixture ofdiastereomers as an orange foam/solid. The diastereomers were separatedby flash chromatography, eluting with 0-100% EtOAc/hexane to afford theminor diastereomer as a gold solid and assigned astrans-3-(2-chloro-5-nitropyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.618 g, 15.13% yield) based on NOE experiments. MS (ESI pos. ion) m/z:330.0 [M+H]. Also obtained 1.56 g of the major diastereomer as a goldsolid and assigned ascis-3-(2-chloro-5-nitropyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(1.56 g, 38.2% yield) based on NOE experiments. MS (ESI pos. ion) m/z:330.0 [M+H].

Step E:trans-3-(5-Nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile

To a solution oftrans-3-(2-chloro-5-nitropyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.150 g, 0.455 mmol) in toluene (3 mL) was added 1-piperidineethanol(0.300 mL, 2.275 mmol), 18-crown-6 (0.180 g, 0.682 mmol) and cesiumcarbonate (0.445 g, 1.365 mmol). The reaction mixture was heated at 80°C. overnight. The reaction mixture was diluted with EtOAc and was washedwith water and brine. The organic layer was concentrated under vacuum.The sample was purified by flash chromatography, eluting with 0-100%90:10:1 DCM/MeOH/NH₄OH: DCM to afford 161 mg of impure product as anorange-red oil. The impure sample was further purified by flashchromatography, eluting with 0-80% 90:10:1 DCM/MeOH/NH₄OH: DCM to affordtrans-3-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.134 g, 69.7% yield) as a dark orange oil. MS (ESI pos. ion) m/z:423.2 [M+H].

Step F:trans-3-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile

To a solution oftrans-3-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.131 g, 0.310 mmol) in MeOH (1.2 mL) was added anhydrous tin (II)chloride (0.235 g, 1.240 mmol). The reaction mixture was heated at 80°C. for 2 hours. The reaction mixture was concentrated under vacuum, andthe remaining residue was dissolved in DCM and was washed with 1Naqueous NaOH followed by brine. The organic layer was dried over sodiumsulfate and concentrated under vacuum. The sample was purified by flashchromatography, eluting with 20-100% 90:10:1 DCM/MeOH/NH₄OH: DCM toaffordtrans-3-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.091 g, 74.8% yield) as a red oil. MS (ESI pos. ion) m/z: 393.3 [M+H].

Step G:(E)-N-(1-(trans-3-Cyano-3-(pyridin-2-yl)cyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

trans-3-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-1-(pyridin-2-yl)cyclobutanecarbonitrile(0.088 g, 0.224 mmol) was dissolved in THF (1.2 mL) and cooled to 0° C.4-Fluorobenzoyl isothiocyanate (0.045 g, 0.247 mmol) was added as a THFsolution. The resulting mixture was stirred at 0° C. for 30 minutes,warmed to 20° C., and stirred for 1 hour. DIPEA (0.047 mL, 0.269 mmol)and EDC (0.052 g, 0.269 mmol) were added to the reaction mixture, andthe reaction was heated at 60° C. for 1 hour. The reaction mixture wasdiluted with DCM and washed with water and brine. The organic layer wasconcentrated under vacuum. The residue was purified by flashchromatography, eluting with 0-100% 90:10:1 DCM/MeOH/NH4OH: DCM toafford(E)-N-(1-(trans-3-cyano-3-(pyridin-2-yl)cyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide(0.053 g, 43.8% yield) as a tan solid. MS m/z (C₃₀H₃₀FN₇O₂); calcd539.61. found 540.2 [M+H].

Example 241

(E)-N-(1-(cis-3-Cyano-3-(pyridin-2-yl)cyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared as previously described for(E)-N-(1-(trans-3-cyano-3-(pyridin-2-yl)cyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide.MS m/z (C₃₀H₃₀FN₇O₂); calcd 539.61. found 540.3 [M+H]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31-1.42 (m, 2H) 1.43-1.55 (m, 4H) 2.33-2.47 (m, 4H)2.57-2.71 (m, 2H) 3.21-3.27 (m, 2H) 4.07-4.23 (m, 2H) 4.34 (t, J=5.92Hz, 2H) 5.36 (quin, J=8.90 Hz, 1H) 6.95 (s, 1H) 7.19-7.34 (m, 2H)7.45-7.55 (m, 1H) 7.77-7.90 (m, 1H) 7.92-8.07 (m, 1H) 8.23 (s, 1H)8.32-8.48 (m, 2H) 8.67-8.85 (m, 1H) 12.77 (br. s., 1H).

Example 242

(E)-N-(1-((5S,8S)-2,4-Dioxo-1,3-diazaspiro[4.5]decan-8-yl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamideStep A. 1,3-Diazaspiro[4.5]decane-2,4,8-trione

A suspension of9,12-dioxa-1,3-diazadispiro[4.2.4.2]tetradecane-2,4-dione (6.33 g, 28.0mmol) in HCl (6N) (28 mL, 168 mmol) and EtOH (66.0 mL) was stirred at RTfor 18 hours. The mixture was partially evaporated (about ½ volume),cooled in an ice bath and brought to a pH of approximately 10. Theaqueous layer was extracted with DCM (2×200 mL), and the aqueous layerconcentrated. The residue was triturated with THF (2×100 mL), and solidswere removed by filtration. The filtrate was evaporated to afford thetitle compound as a white solid.

Step B. 8-Amino-1,3-diazaspiro[4.5]decane-2,4-dione

To a suspension of 1,3-diazaspiro[4.5]decane-2,4,8-trione (5.00 g, 27.4mmol) in MeOH (91 mL) was added ammonium acetate (6.35 g, 82 mmol), andthe mixture was stirred at RT for 25 minutes. To the suspension wasadded sodium cyanoborohydride (5.17 g, 82 mmol), and the mixture wasstirred at RT. After 90 minutes, the flask was cooled, and the contentswere quenched by careful addition of aqueous concentrated HCl, adjustingthe pH to 7 with solid NaHCO₃. The mixture was filtered through a pad ofCelite® brand filter aid and concentrated in vacuo. The material wasused directly in the next step.

Step C.8-(5-(Hydroxymethyl)-2-nitrophenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione

The title compound was prepared using a method analogous to that used inthe preparation of cis-methyl4-(3-nitropyridin-4-ylamino)cyclohexanecarboxylate starting from8-amino-1,3-diazaspiro[4.5]decane-2,4-dione.

Step D.8-(5-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione

The title compound was prepared using a method analogous to that used inthe preparation of cis-methyl4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylatestarting from8-(5-(hydroxymethyl)-2-nitrophenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione.

Step E.8-(2-Amino-5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)phenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione

The title compound was synthesized using a method analogous to thepreparation ofcis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamidestarting from8-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione.

Step F.(E)-N-(1-((5S,8S)-2,4-Dioxo-1,3-diazaspiro[4.5]decan-8-yl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared from8-(2-amino-5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)phenylamino)-1,3-diazaspiro[4.5]decane-2,4-dione(467 mg, 1.087 mmol) using a method analogous to that used in thepreparation of(E)-4-fluoro-N-(1-((1S,4S)-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide,and obtained as a white solid. MS m/z (C₃₁H₃₇FN₆O₄), calcd 576.66. found577 [M+H].

Example 243

(E)-N-(1-(cis-4-(Azetidin-3-ylcarbamoyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared fromcis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylicacid using a method analogous to that used in the preparation of(E)-N-(1-(cis-4-(cis-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide.MS m/z (C₃₃H₄₃FN₆O₃), calcd 590.3. found 591.2 [M+H].

Example 244

(E)-3-(N-Allylsulfamoyl)-N-(1-(trans-4-carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamideStep A: trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylicacid hydrochloride

Trans-4-Aminocyclohexanecarboxylic acid (5.01 g, 35.0 mmol) andpotassium carbonate (4.83 g, 35.0 mmol) were dissolved in water (20.00mL). 2,4-Dichloro-5-nitropyridine (6.75 g, 35.0 mmol) was added to thereaction mixture as a dioxane (40 mL) solution. The reaction mixture wasstirred at 80° C. for 8 hours. The reaction mixture was concentratedunder vacuum to remove the dioxane and the remaining aqueous solutionwas acidified with aqueous 2N HCl (approximately pH 2-3). A precipitateformed which was collected on a glass frit washing well with water andthen with DCM. The solid was dried under high vacuum at 37° C. 8.79 g oftrans-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride (74.8% yield) was collected as a yellow solid. Mass cal'd:299.1; MS (ESI pos. ion) m/z: 300.0 [M+H].

Step B.Trans-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxamide

Trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acidhydrochloride (5.00 g, 14.87 mmol) was suspended in THF (30 mL), and themixture was cooled to 0° C. Thionyl chloride (4.34 mL, 59.5 mmol) wasslowly added via syringe. The suspension became thicker and lighteryellow in color. The reaction mixture was stirred at 0° C. for 15minutes and then warmed to 20° C. and stirred for an additional 2 hours.The reaction was concentrated to dryness under vacuum. The remainingsolid was concentrated from THF again and dried under high vacuum. Thesolid was resuspended in THF (75 mL), cooled to 0° C. and then ammoniagas was bubbled through the mixture for approximately 5 minutes. Thereaction mixture was stirred at 0° C. for 30 minutes then warmed to 20°C. and stirred overnight. A precipitate was present in the reactionmixture. Water was added to the mixture and stirring was continued forabout 15 minutes. The mixture was filtered and the solid was washed withwater and THF and dried under high vacuum to yield 3.93 g of product asa yellow solid. The filtrate was also extracted with DCM, and theorganic layer was dried over sodium sulfate and concentrated undervacuum to yield an additional 981 mg of product as a yellow solid. Masscal'd: 298.1; MS (ESI pos. ion) m/z: 299.0 [M+H].

Step C.trans-4-(5-Nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

Trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (3.00g, 10.04 mmol) was suspended in toluene (30 mL). 1-Piperidine ethanol(6.62 mL, 50.2 mmol), 18-crown-6 (3.98 g, 15.06 mmol) and cesiumcarbonate (9.82 g, 30.1 mmol) were then added to the reaction. Theresulting reaction mixture was heated at 80° C. overnight followed byadditional heating at 90° C. for 8 hours. The reaction mixture wasdiluted with DCM and washed with water and brine. The organic layer wasconcentrated under vacuum to yield 6.43 g of crude material as a yellowoil/residue. The sample was purified by flash chromatography, elutingwith 0-100% 90:10:1 dichloromethane/methanol/NH₄OH:dichloromethane toafford 1.62 g oftrans-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide(41.2% yield) as a yellow solid. Mass cal'd: 391.2; MS (ESI pos. ion)m/z: 392.2 [M+H].

Step D.trans-4-(5-Amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide

The title compound was prepared as previously described forcis-4-(5-amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide.The sample was purified via trituration with DCM to yield 914 mg oftrans-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide(61.1% yield) as a light red solid. Mass cal'd: 361.2; MS (ESI pos. ion)m/z: 362.2 [M+H].

Step E.(E)-3-(N-Allylsulfamoyl)-N-(1-(trans-4-carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared as previously described for(E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide.The sample was purified by flash chromatography, eluting with 20-100%90:10:1 DCM/MeOHl/NH₄OH:DCM followed by trituration with DCM to afford77 mg of(E)-3-(N-allylsulfamoyl)-N-(1-(trans-4-carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(76% yield) as a pale yellow solid. Mass cal'd: 609.3; MS (ESI pos. ion)m/z: 610.0 [M+H].

Example 245

(E)-3-(N-Allylsulfamoyl)-N-(1-((1R,4R)-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in an analogous manner to Example 244.The sample was purified by flash chromatography, eluting with 0-100%90:10:1 DCM/MeOH/NH₄OH:DCM followed by trituration with ACN to afford 58mg of(E)-3-(N-allylsulfamoyl)-N-(1-(trans-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(46.6% yield) as a white solid. Mass cal'd: 623.3; MS (ESI pos. ion)m/z: 624.3 [M+H].

Example 246

(E)-4-Fluoro-N-(1-(trans-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in an analogous manner to Example 244.The sample was purified by flash chromatography, eluting with 0-100%90:10:1 DCM/MeOH/NH₄OH:DCM followed by trituration with ACN to afford 87mg of(E)-4-fluoro-N-(1-(trans-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.087 g, 0.166 mmol, 83% yield) as a white solid. Mass cal'd: 522.3; MS(ESI pos. ion) m/z: 523.2 [M+H].

Example 247

(E)-N-(1-(trans-4-Carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3,5-difluorobenzamide

The title compound was prepared in an analogous manner to Example 244.The sample was purified by flash chromatography, eluting with 10-100%90:10:1 DCM/MeOH/NH₄OH:DCM followed by trituration with DCM and then ACNto afford 63 mg of(E)-N-(1-(trans-4-carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3,5-difluorobenzamide(0.063 g, 0.120 mmol, 72.1% yield) as a white solid. Mass cal'd: 526.2;MS (ESI pos. ion) m/z: 527.2 [M+H].

Example 248

(E)-N-(1-(trans-4-Carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared in an analogous manner to Example 244.The sample was purified by flash chromatography, eluting with 0-100%90:10:1 DCM/MeOH/NH₄OH:DCM to afford 27 mg of(E)-N-(1-(trans-4-carbamoylcyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide(0.027 g, 0.053 mmol, 32.0% yield) as a pale yellow solid. Mass cal'd:508.3; MS (ESI pos. ion) m/z: 509.2 [M+H].

Example 249

(E)-3,5-Difluoro-N-(1-(trans-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide

The title compound was prepared in an analogous manner to Example 245.The sample was purified by flash chromatography, eluting with 10-100%90:10:1 DCM/MeOH/NH₄OH:DCM followed by trituration with ACN to afford 51mg of(E)-3,5-difluoro-N-(1-(trans-4-(methylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide(0.051 g, 0.094 mmol, 47.2% yield) as a white solid. Mass cal'd: 540.3;MS (ESI pos. ion) m/z: 541.2 [M+H].

Example 250

(E)-N-(1-(trans-3-(3-Bromophenyl)-3-cyanocyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamideStep A. 1-(3-Bromophenyl)-3-oxocyclobutanecarbonitrile

To 3-bromophenylacetonitrile (7.55 g, 38.5 mmol) and1,3-dibromo-2,2-dimethyoxypropane (10.09 g, 38.5 mmol) in dry DMSO (100ml) was added in two portions sodium hydride (3.23 g of 60% dispersionin oil, 81 mmol) while the mixture was cooled in a water bath. Themixture was stirred at RT for 10 minutes, and heated at 60° C. in an oilbath for 6 hours. The reaction was diluted with water and extracted withEtOAc. The organic layer was separated, washed with water and thesolvent removed. The residual red oil was eluted through a short pad ofsilica, eluent 10% EtOAc/Hexane. The resulting ketal was dissolved inacetone (100 ml) and 1N aqueous HCl (10 ml) and heated at reflux for 6hours under a nitrogen atmosphere. The solvent was removed and theresidue was neutralized by treatment with aqueous NaHCO₃ and extractedwith EtOAc. The solvent was removed and the residue was chromatographed(SiO₂, eluent 10% EtOAc in hexane) to give a yellow oil which solidifiedon drying under vacuum.

Step B. 1-(3-Bromophenyl)-3-hydroxycyclobutanecarbonitrile

1-(3-Bromophenyl)-3-oxocyclobutanecarbonitrile (2.00 g, 8.00 mmol) wasdissolved in DCM (15 mL) and MeOH (15.00 mL), and the mixture was cooledto 0° C. Sodium borohydride (0.333 g, 8.80 mmol) was added to thereaction mixture, and stirring was continued at 0° C. for 1.5 hours. Thereaction mixture was quenched with water at 0° C. then warmed to RT. DCMwas added, and the mixture was washed with water and brine. The organiclayer was dried over sodium sulfate and concentrated under vacuum toafford 2.02 g of 1-(3-bromophenyl)-3-hydroxycyclobutanecarbonitrile(2.02 g, 8.01 mmol, 100% yield) as a pale yellow oil. Mass cal'd:250.99; MS (ESI pos. ion) m/z: 252.0 [M+H].

Step C.(E)-N-(1-(trans-3-(3-Bromophenyl)-3-cyanocyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared from1-(3-bromophenyl)-3-hydroxycyclobutanecarbonitrile in an analogousmanner to Example 240. The sample was purified by flash chromatography,eluting with 0-100% 90:10:1 DCM/MeOH/NH₄OH:DCM followed by theseparation of diastereomers via SFC chromatography eluting with 45% MeOH(0.1% DEA)/CO₂, 100 bar to afford 116 mg of(E)-N-(1-(trans-3-(3-bromophenyl)-3-cyanocyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide(0.116 g, 0.188 mmol, 24.9% yield) as a tan solid. Mass cal'd: 616.2; MS(ESI pos. ion) m/z: 617.0 [M+H].

Example 251

(E)-N-(1-(trans-3-(3-Bromophenyl)-3-carbamoylcyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

(E)-N-(1-(trans-3-(3-Bromophenyl)-3-cyanocyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide(0.055 g, 0.089 mmol) was dissolved in concentrated sulfuric acid (0.570μL, 10.69 μmol) and then stirred at 20° C. for 2 hours. The reactionmixture was slowly poured into cold saturated aqueous sodium carbonate.A precipitate formed which was collected on a glass frit, washing withwater, acetonitrile and dichloromethane. The solid was transferred to aflask with DCM/MeOH and concentrated under vacuum. The residue was thendried under high vacuum to afford 37 mg of(E)-N-(1-(trans-3-(3-bromophenyl)-3-carbamoylcyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide(0.037 g, 0.058 mmol, 65.4% yield) as a tan solid. Mass cal'd: 634.2; MS(ESI pos. ion) m/z: 635.0 [M+H].

Example 252

(E)-N-(1-(cis-3-(3-Bromophenyl)-3-carbamoylcyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide

The title compound was prepared in an analogous manner to Example 251 toafford 54 mg of(E)-N-(1-(cis-3-(3-bromophenyl)-3-carbamoylcyclobutyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-4-fluorobenzamide.Mass cal'd: 634.2; MS (ESI pos. ion) m/z: 635.0 [M+H].

ALK Inhibition in Enzyme Assay

The cytoplasmic domain (amino acids 1058-1620) of wild-type human ALKwas expressed in SF9 cells as an N-terminal GST fusion protein. Kinaseactivity of the purified protein was assessed using a Lance® TR-FRETassay. The kinase reaction was performed in a 384-well microtiter plateusing 2 nM enzyme in 20 mM HEPES (pH 7.5), 0.05% BSA, 2 mM DTT, 10 mMMgCl₂, 1 μM peptide substrate (Biotin-Ahx-EQEDEPEGIYGVLF-OH)(SEQ ID NO:1), and ATP at 40 μM (the Km apparent). The reaction was allowed toproceed for 90 minutes at room temperature and was then terminated with20 mM EDTA in 50 mM Tris (pH 7.5), 100 mM NaCl, 0.05% BSA, and 0.1%Tween-20. Phosphorylation of the peptide substrate was detected usingthe Lance® detection reagents streptavidin-allophycocyanin (SA-APC) andEu-W1024 anti-phosphotyrosine antibody (PT66) from Perkin Elmer LifeSciences (Waltham, Mass.). The plates were read on a RUBY star platereader (BMG LABTECH, Cary, N.C.) with an excitation wavelength of 320nm. Emission was monitored at 615 nm and 665 nm, with increased emissionat 665 nm indicative of peptide phosphorylation. Compound IC₅₀ valueswere calculated from the magnitude of signal in the 655 nm emissionchannel and were expressed as the mean of three replicates.

The following table includes ALK IC₅₀ values obtained using theprocedure set forth above for the Example compounds described herein.

Table of ALK IC₅₀ values of Example Compounds ALK IC₅₀ Example (μM)^(a)1 ++++ 2 ++++++ 3 ++++++ 4 ++++++ 5 ++++++ 6 ++++++ 7 ++++++ 8 ++++++ 9++++++ 10 ++++ 11 ++++++ 12 ++++ 13 ++++ 14 ++++++ 15 ++++++ 16 +++++ 17++++++ 18 ++++++ 19 ++++++ 20 ++++++ 21 ++++++ 22 ++++++ 23 ++++++ 24++++++ 25 +++ 26 ++++++ 27 ++++ 28 ++++ 29 ++++++ 30 ++++++ 31 ++++++ 32++++++ 33 ++++++ 34 ++++ 35 ++++++ 36 ++++ 37 ++++ 38 ++++++ 39 ++++++40 +++++ 41 ++++++ 42 +++ 43 ++++++ 44 ++++++ 45 ++++++ 46 ++++++ 47++++++ 48 ++++++ 49 +++++ 50 ++++++ 51 ++++++ 52 ++++++ 53 ++++++ 54++++++ 55 NA^(b) 56 ++++ 57 ++++++ 58 ++++++ 59 ++++++ 60 +++ 61 ++++++62 +++++ 63 +++++ 64 ++++ 65 +++ 66 ++++ 67 ++++ 68 ++ 69 ++++ 70 +++ 71++++ 72 ++++++ 73 ++++ 74 ++++++ 75 ++++ 76 +++ 77 ++++++ 78 ++++++ 79+++ 80 ++++++ 81 ++++ 82 +++ 83 ++++ 84 ++++ 85 ++++++ 86 ++ 87 +++++ 88+++++ 89 ++++++ 90 ++++++ 91 ++++++ 92 ++++++ 93 +++ 94 +++++ 95 ++++++96 ++++++ 97 +++++ 98 ++++++ 99 ++++ 100 +++++ 101 ++++++ 102 ++++ 103++++++ 104 ++++ 105 +++ 106 ++++++ 107 ++++++ 108 ++++++ 109 +++ 110 +++111 ++++++ 112 ++ 113 ++++ 114 +++++ 115 ++++++ 116 +++++ 117 +++++ 118++++++ 119 ++++++ 120 ++++ 121 +++++ 122 ++++ 123 ++++++ 124 ++++ 125++++++ 126 ++++++ 127 ++++++ 128 ++++++ 129 ++++++ 130 ++++++ 131 ++++132 ++++ 133 ++++ 134 +++++ 135 ++++++ 136 +++ 137 ++++++ 138 ++++++ 139++++++ 140 ++++++ 141 ++++++ 142 ++++++ 143 ++++++ 144 ++++++ 145 ++++++146 ++++++ 147 ++++++ 148 ++++++ 149 ++++++ 150 ++++++ 151 ++++++ 152++++++ 153 ++++++ 154 ++++++ 155 ++++++ 156 ++++++ 157 ++++++ 158 ++++++159 ++++++ 160 ++++++ 161 ++++++ 162 ++++++ 163 ++++++ 164 ++++++ 165++++++ 166 ++++++ 167 ++++++ 168 ++++++ 169 ++++++ 170 ++++++ 171 ++++++172 ++++++ 173 ++++++ 174 ++++++ 175 ++++++ 176 ++++++ 177 ++++++ 178++++++ 179 ++++++ 180 ++++++ 181 ++++++ 182 ++++++ 183 ++++++ 184 ++++++185 ++++++ 186 ++++++ 187 ++++++ 188 ++++++ 189 ++++++ 190 ++++++ 191++++++ 192 ++++++ 193 ++++++ 194 ++++++ 195 ++++++ 196 ++++++ 197 ++++++198 ++++++ 199 ++++++ 200 ++++++ 201 ++++++ 202 ++++ 203 ++++ 204 ++++++205 ++++++ 206 +++++ 207 +++++ 208 ++++++ 209 ++++++ 210 ++++ 211 ++++++212 ++++++ 213 ++++++ 214 ++++++ 215 ++++++ 216 ++++++ 217 ++++++ 218++++++ 219 ++++++ 220 ++++++ 221 ++++++ 222 ++++++ 223 ++++++ 224 ++++++225 ++++++ 226 ++++++ 227 +++++ 228 ++++ 229 +++++ 230 ++++++ 231 ++++++232 ++++++ 233 +++++ 234 ++++ 235 ++++++ 236 ++++++ 237 ++++ 238 ++++++239 ++++++ 240 +++ 241 ++++ 242 ++++ 243 ++++++ 244 +++++ 245 +++++ 246++++ 247 +++ 248 +++ 249 +++ 250 ++++ 251 +++++ 252 +++ ^(a)IC₅₀Ranges: + IC₅₀ > 10 μM ++ 5 μM ≦ EC₅₀ ≦ 10 μM +++ 1 μM ≦ EC₅₀ < 5 μM++++ 0.1 μM ≦ EC₅₀ < 1 μM +++++ 0.05 μM ≦ EC₅₀ < 0.1 μM ++++++ EC₅₀ <0.05 μM ^(b)Not Applicable

All publications and patent applications cited in this specification arehereby incorporated by reference herein in their entireties and for allpurposes as if each individual publication or patent application werespecifically and individually indicated as being incorporated byreference and as if each reference was fully set forth in its entirety.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1-35. (canceled)
 36. A method of treating cancer, the method comprising:administering to a subject an effective amount of the compound or apharmaceutical compositions comprising the compound of Formula I:

or the pharmaceutically acceptable salt thereof, tautomer thereof, thepharmaceutically acceptable salt of the tautomer, or the stereoisomer ofany of the foregoing, wherein. R¹ is —H; R² is —H; R³ is —H; X isselected from CR⁴; R⁴ is —H; Y is selected from a C₃-C₁₂ cycloalkyl or a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom O, S, or N; wherein the C₃-C₁₂ cycloalkyl and the 3-10 memberedheterocyclyl may be monocyclic, bicyclic, or tricyclic, and furtherwherein the C₃-C₁₂ cycloalkyl and the 3-10 membered heterocyclylcomprise a substituent selected from —C(═O)NH₂, —C(═O)NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-F,—C(═O)NH—(C₂-C₄)alkenyl, —C(═O)N((C₁-C₆)alkyl)₂, —C(═O)NH—OH,—C(═O)NH—O—(C₁-C₆)alkyl, —C(═O)NH—Y″, —C(═O)—(C₁-C₄)alkylene-CF₃,—C(═O)N—(C₁-C₄)alkylene-F, —C(═O)—(C₂-C₄)alkenyl,—C(═O)—(C₁-C₄)alkylene-NH₂, —C(═O)—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-Y″,—C(═O)—(C₁-C₆)alkyl, —C(═O)—Y″, —CO₂H, —C(═O)—O—(C₁-C₆)alkyl,—C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),and —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl; and wherein Y optionally furthercomprises 1 or 2 substituents selected from Y′, —F, —Cl, —Br, —I, —C≡N,—NO₂, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, —OCHF₂, —CF₃,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₆)alkyl,—NHC(═O)—(C₁-C₆)alkyl, —C(═O)NH₂, —C(═O)NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-F,—C(═O)NH—(C₂-C₄)alkenyl, —C(═O)N((C₁-C₆)alkyl)₂, —C(═O)NH—OH,—C(═O)NH—O—(C₁-C₆)alkyl, —C(═O)NH—Y″, —C(═O)—(C₁-C₄)alkylene-CF₃,—C(═O)N—(C₁-C₄)alkylene-F, —C(═O)—(C₂-C₄)alkenyl,—C(═O)—(C₁-C₄)alkylene-NH₂, —C(═O)—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —C(═O)NH—(C₁-C₄)alkylene-Y″,—C(═O)—(C₁-C₆)alkyl, —C(═O)—Y″, —CO₂H, —C(═O)—O—(C₁-C₆)alkyl,—C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),and —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₆)alkyl), —SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₄)alkenyl),—SO₂NH((C₂-C₄)alkynyl), —SO₂NH—Y″, —SO₂NH—(C₁-C₄)alkylene-OH,—SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂—Y″,—SO—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-NH—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂-(C₁-C₄)alkylene-OH,—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, or —(C₁-C₄)alkylene-C(═O)—OH,wherein two substituents on a carbon ring member of the Y cycloalkyl orheterocyclyl may join to form a 3-7 membered cycloalkyl group or a 3-7membered heterocyclyl group that comprises 1 to 3 heteroatoms selectedfrom N, O, or S; and further wherein 1 or 2 carbon atom ring members ofthe 3-7 membered cycloalkyl or the 3-7 membered heterocyclyl groupformed from the two substituents on the carbon ring member of the Ycycloalkyl or heterocyclyl may be double bonded to an O atom; Y′ may beabsent or is a C₆-C₁₀ aryl, a 5-10 membered heteroaryl comprising 1, 2,3, or 4 heteroatoms independently selected from O, S, or N, or a 3-7membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O,S, or N, wherein the C₆-C₁₀ aryl, the 5-10 membered heteroaryl, or the3-7 membered heterocyclyl Y′ groups are unsubstituted or are optionallysubstituted with 1, 2, or 3 substituents independently selected from —F,—Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl),—N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; Y″ may beabsent or is selected from a C₃-C₁₀ cycloalkyl; a 3-10 memberedheterocyclyl comprising 1, 2, or 3 heteroatoms selected from N, O, andS; a C₆-C₁₀ aryl; or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4heteroatoms independently selected from N, O, or S; wherein the C₃-C₁₀cycloalkyl and the 3-10 membered heterocyclyl may be monocyclic orbicyclic, and further wherein the C₃-C₁₀ cycloalkyl, the 3-10 memberedheterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroaryl Y″ groupsare unsubstituted or are optionally substituted with 1, 2, or 3substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH,—NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂,—C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂,—SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl,—NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; W is selectedfrom —(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl, —(CR^(a)R^(a′))_(q)—O—W′,—O—(CR^(a)R^(a′))_(q)—W′, —O—(CR^(a)R^(a′))_(q)—OH,—O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—OH,—(CR^(a)R^(a′))_(q)—O—(CR^(a)R^(a′))_(q)—O—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—SH, —(CR^(a)R^(a′))_(q)—S—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—S—W′, —S—(CR^(a)R^(a′))_(q)—W′,—(CR^(a)R^(a′))_(q)—S(O)₂—(C₁-C₆)alkyl, —(CR^(a)R^(a′))_(q)—S(O)₂—W′,—S(O)₂—(CR^(a)R^(a′))_(q)—W′, —(CR^(a)R^(a′))_(q)—NH₂,—(CR^(a)R^(a′))_(q)—NH—(C₁-C₆)alkyl,—(CR^(a)R^(a′))_(q)—N—((C₁-C₆)alkyl,)₂,—(CR^(a)R^(a′))_(q)—N⁺—((C₁-C₆)alkyl,)₃, —(CR^(a)R^(a′))_(q)—NH—W′,—(CR^(a)R^(a′))_(q)—NH—(CR^(a)R^(a′))_(q)—OH, —NH—(CR^(a)R^(a′))_(q)—W′,or —(CR^(a)R^(a′))_(q)—W′; W′ may be absent or is selected from a C₃-C₁₀cycloalkyl; a 3-10 membered heterocyclyl comprising 1, 2, or 3heteroatoms selected from N, O, and S; a C₆-C₁₀ aryl; or a 5-10 memberedheteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, or S; wherein the C₃-C₁₀ cycloalkyl and the 3-10 memberedheterocyclyl may be monocyclic or bicyclic, and further wherein theC₃-C₁₀ cycloalkyl, the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, orthe 5-10 membered heteroaryl W′ groups are unsubstituted or areoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CH(CF₃)(OH),—(C₁-C₄)alkylene-NH₂, —(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃,—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl),—C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl),—SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, —SO—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl,—CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂,—C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —C(═O)NH—(C₁-C₄)alkylene-OH,—C(═O)NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH—(C₁-C₄)alkylene-O—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —SO₃H,—OCF₃, —OCHF₂, or —C(═O)—W″; and further wherein W′ may include 0, 1, or2 ═O groups when W′ is a C₃-C₁₀ cycloalkyl or a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; W″ may be absent or is selected from aC₃-C₁₀ cycloalkyl; a 3-10 membered heterocyclyl comprising 1, 2, or 3heteroatoms selected from N, O, and S; a C₆-C₁₀ aryl; or a 5-10 memberedheteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, or S; wherein the C₃-C₁₀ cycloalkyl and the 3-10 memberedheterocyclyl may be monocyclic or bicyclic, and further wherein theC₃-C₁₀ cycloalkyl, the 3-10 membered heterocyclyl, the C₆-C₁₀ aryl, orthe 5-10 membered heteroaryl W″ groups are unsubstituted or areoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂, —NH((C₁-C₄)alkyl),—N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —SH,—S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and further wherein W″ may include 0,1, or 2 ═O groups when W″ is a C₃-C₁₀ cycloalkyl or a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; the subscript q is, in each instance,independently selected from 0, 1, 2, 3, or 4; R^(a) is, in eachinstance, independently selected from —H, —CH₃, —CH₂CH₃, —F, —CF₃, or—C≡N; R^(a′) is, in each instance, independently selected from —H, —CH₃,—CH₂CH₃, —F, —CF₃, or —C≡N; or R^(a) and R^(a′) may join to form acyclopropyl ring together with the carbon atom to which they areattached; Z is selected from —OMe or —NH-cyclohexyl; or a phenyl,pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinylgroup; wherein the —NH-cyclohexyl, phenyl, pyridyl, benzothiophenyl,thiazolyl, pyradizinyl, pyrimidinyl, indolyl, cyclohexyl, morpholinyl,pyrrolidinyl, piperazinyl, or piperidinyl group is unsubstituted or isoptionally substituted with 1, 2, or 3 substituents independentlyselected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —CF₃, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂,—NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₆)alkyl),—C(═O)N((C₁-C₆)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₆)alkyl),—SO₂N((C₁-C₆)alkyl)₂, —SO₂NH((C₂-C₆)alkenyl), —SO₂NH((C₂-C₆)alkynyl),—SO₂NH—(C₁-C₄)alkylene-OH, —SO₂NH—(C₁-C₄)alkylene-O—(C₁-C₆)alkyl,—NHSO₂—(C₁-C₆)alkyl, —NHC(═O)—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl,—SO—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₆)alkyl,—C(═O)—(C₁-C₆)alkyl, —CO₂H, —C(═O)—O—(C₁-C₆)alkyl,—C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₆)alkyl),—C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₆)alkyl)₂,—(C₁-C₄)alkylene-C(═O)—(C₁-C₆)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₆)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH,—O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂.
 37. The methodof claim 36, wherein Z is an unsubstituted or substituted phenyl,pyridyl, benzothiophenyl, thiazolyl, pyradizinyl, pyrimidinyl, indolyl,cyclohexyl, morpholinyl, pyrrolidinyl, piperazinyl, or piperidinylgroup, or a pharmaceutically acceptable salt thereof, tautomer thereof,a pharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing.
 38. The method of claim 36, wherein Z is anunsubstituted or substituted phenyl or pyridyl, or a pharmaceuticallyacceptable salt thereof, tautomer thereof, a pharmaceutically acceptablesalt of the tautomer, or a stereoisomer of any of the foregoing.
 39. Themethod of claim 36, wherein Z is selected from

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 40. The method of claim 36, wherein Z is selectedfrom

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 41. The method of claim 36, wherein Y issubstituted cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl,piperidinyl, pyrrolidinyl, azetidinyl, adamantyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[2.2.1]heptyl,bicyclo[3.1.1]heptyl, or bicyclo[2.1.1]hexyl, or a pharmaceuticallyacceptable salt thereof, tautomer thereof, a pharmaceutically acceptablesalt of the tautomer, or a stereoisomer of any of the foregoing.
 42. Themethod of claim 41, wherein Y is substituted cyclohexyl, or apharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing.
 43. The compound of claim 36, wherein Y isselected from

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 44. The method of claim 36, wherein Y is selectedfrom

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 45. The method of claim 36, wherein Y is selectedfrom

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 46. The compound of claim 45, wherein Y is

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 47. The compound of claim 36, wherein W isselected from —CH₂OCH₃, —CH₂OCH₂CH₂OH, —CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OH,—OCH₂CH₂OMe, —W′, —CH₂W′, —OW′, —OCH₂W′, —OCH₂CH₂W′, —OCH₂CH₂CH₂W′,—NHW′, —NHCH₂W′, —NHCH₂CH₂W′, —NHCH₂CH₂CH₂W′, or —W′—C(═O)—W″; whereinW′, if present, is selected from a 3-10 membered heterocyclyl comprising1 or 2 heteroatoms selected from N, O, and S; a C₆-C₁₀ aryl; or a 5-10membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independentlyselected from N, O, or S; wherein the 3-10 membered heterocyclyl W′group may be monocyclic or bicyclic, and further wherein the 3-10membered heterocyclyl, the C₆-C₁₀ aryl, or the 5-10 membered heteroarylW′ groups are unsubstituted or are substituted with 1, 2, 3, or 4substituents independently selected from —F, —Cl, —Br, —(C₁-C₆)alkyl,—CH(CF₃)(OH), —(C₁-C₄)alkylene-NH₂,—(C₁-C₄)alkylene-NH—(C₁-C₄)alkylene-CF₃, —C(═O)NH₂, —SO₂—(C₁-C₆)alkyl,—CF₃, —CO₂H, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl,—(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH,—(C₁-C₄)alkylene-OH, —OH, —O—(C₁-C₆)alkyl, or —SO₃H; and further whereinW′ may include 0, 1, or 2 ═O groups when W′ is a 3-10 memberedheterocyclyl, and further wherein the ═O groups may be bonded to a ringcarbon atom or a ring S atom; and further wherein W″, if present, is a3-10 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selectedfrom N, O, and S, wherein the 3-10 membered heterocyclyl W″ group may bemonocyclic or bicyclic, and further wherein the 3-10 memberedheterocyclyl W″ group is unsubstituted or is optionally substituted with1, 2, 3, or 4 substituents independently selected from —F, —Cl, —Br, —I,—C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OH, —NH₂,—NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —CF₃, —CO₂H,—C(═O)—O—(C₁-C₄)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂, or apharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing.
 48. The method of claim 36, wherein W is selectedfrom —OMe, —SO₂Me, —CH₂OMe, —OCH₂CH₂OH, —OCH₂CH₂OMe, or a group selectedfrom

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 49. The method of claim 36, wherein W is selectedfrom —SO₂Me, —CH₂OMe, —OCH₂CH₂OH, —OCH₂CH₂OMe, or a group selected from

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 50. The method of claim 36, wherein W is selectedfrom

or a pharmaceutically acceptable salt thereof, tautomer thereof, apharmaceutically acceptable salt of the tautomer, or a stereoisomer ofany of the foregoing, wherein the symbol

, when drawn across a bond, indicates the point of attachment to therest of the molecule.
 51. The method of claim 36, wherein the cancer isdue to abnormal cell growth and is selected from the group consisting ofsmall cell lung carcinoma, non-small cell lung carcinoma, liver cancer,lung cancer, sarcoma, stomach cancer, cholangiocarcinoma, mesothelioma,prostate cancer. lung cancer, bone cancer, pancreatic cancer, skincancer, cancer of the head or neck, cutaneous or intraocular melanoma,uterine cancer, ovarian cancer, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostatecancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, neoplasms of the central nervous system (CNS),primary CNS lymphoma, spinal axis tumors, brain stem glioma, andpituitary adenoma.
 52. The method of claim 51, wherein the cancer isselected from the group consisting of small cell lung carcinoma,non-small cell lung carcinoma, esophageal cancer, kidney cancer,pancreatic cancer, melanoma, bladder cancer, breast cancer, coloncancer, liver cancer, lung cancer, sarcoma, stomach cancer,cholangiocarcinoma, mesothelioma, or prostate cancer.
 53. The method ofclaim 36, wherein the subject has a cancer that expresses an ALK fusionprotein.
 54. The method of claim 53, wherein the ALK fusion protein isEML4-ALK fusion protein or NPM-ALK fusion protein.
 55. The method ofclaim 54, wherein the subject is a human cancer patient, and the canceris selected from adenocarcinoma, lung cancer, non-small cell lungcarcinoma, breast cancer, colorectal cancer, lymphoma, neuroblastoma,ovarian cancer, mesothelioma, melanoma, glioblastoma, diffuse largeB-cell lymphomas, systemic histiocytosis, or inflammatorymyofibroblastic tumors.
 56. The method of claim 55, wherein the canceris non-small cell lung carcinoma.